Vanderbilt University School of
Pao, William , MD, PhD
Adjunct Professor of Medicine
Phone Number: 615-322-4967
777 Preston Research Building 2220 Pierce Avenue 37232-6307
Lung cancer, cancer biology, genomics, EGFR, EGFR tyrosine kinase inhibitors, acquired resistance, targeted therapies, molecular medicine, mutation, signal transduction
The Pao Laboratory aims to perform translational research in the area of solid tumor biology, using lung cancer as a paradigm. The overall goal is to develop molecularly-tailored treatments for patients with lung cancer.
Lung cancer is the leading cause of cancer-related death in the U.S and worldwide. Most cases arise in former or current smokers, but about 10% of cases also occur in individuals who smoked less than 100 cigarettes in a lifetime (?never smokers?). Lung cancers are currently classified by histopathological techniques as either small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). In North America, adenocarcinoma (a type of NSCLC) is the most frequent type of histological tumor, accounting for 40% of all cases of lung cancer.
New ?targeted? epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like gefitinib (Iressa) and erlotinib (Tarceva) have given us a window of opportunity to elucidate clinically relevant molecular subsets of lung adenocarcinomas. For example, clinical trials have shown that gefitinib has an overall response rate of 10% in American and European populations, and 28% in Japanese patients. Retrospective analyses suggested that gefitinib is most efficacious in ?never smokers? with adenocarcinoma histology. Such findings can now be largely accounted for by research from our group and others showing the relatively high incidence of mutations in the gene encoding EGFR in these respective populations and the association of EGFR mutations with increased sensitivity to both gefitinib and erlotinib.
While EGFR mutations are common in tumors from never smokers, mutations in KRAS, which encodes a signaling molecule downstream of EGFR, more commonly occur in individuals with substantial cigarette use. Moreover, EGFR and KRAS mutations appear to be mutually exclusive, suggesting that EGFR and KRAS mutations within lung epithelia are equivalent in their tumorigenic effects. We found that mutations in KRAS are associated with primary resistance to these drugs. This suggests that pre-treatment mutational profiling of both EGFR and KRAS may help guide treatment decisions regarding the use of these agents.
Unfortunately, virtually all patients who initially respond to gefitinib and erlotinib eventually develop acquired resistance. We have shown that tumor cells from patients whose disease progresses after initial responses on therapy with these agents frequently harbor second-site mutations in EGFR. The predominant second mutation substitutes methionine for threonine at position 790 in EGFR, which is predicted to block binding of gefitinib and erlotinib to the ATP-binding pocket of the kinase. Interestingly, the T790M amino acid change is analogous to changes seen in other kinases targeted by a related kinase inhibitor, imatinib (Gleevec), in patients that develop acquired resistance to that drug. Using a genomic approach, we have also recently found that tumor samples from patients with acquired resistance to gefitinib or erlotinib harbor amplification of MET, which encodes another tyrosine kinase. MET amplification appears to occur independently of T790M mutations. Importantly, MET inhibitors are currently being developed in the clinic.
The Pao Laboratory is now focused on the following:
1) Defining further molecular subsets of lung cancers, based primarily upon mutational profiling of the oncogenome in tumor samples.
2) Elucidating other mechanisms of sensitivity and resistance to EGFR inhibitors in lung cancer. For example, we recently showed that in drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors. These data imply that the intrinsic pathway of caspase activation may influence sensitivity and/or resistance of EGFR mutant lung tumor cells to EGFR kinase inhibition.
3) Identifying ways to overcome resistance to gefitinib and erlotinib. We have generated mouse lung tumor models driven by EGFR T790M mutants and which are resistant to erlotinib. We are now using these models to uncover agents and strategies that overcome acquired resistance to the T790M amino acid change.
The identification of genetic abnormalities that initiate and sustain cancers has paved the way to a new era of personalized anti-cancer therapies which are more effective than current approaches with fewer side effects. We aim to shape the practice of cancer medicine, envisioning a day when anti-cancer treatment will be assigned according to the genetic makeup of patients' tumors rather than on an empiric basis.
Abramson, RG, Abramson, VG, Chan, E, Horn, L, Keedy, VL, Pao, W, Sosman, JA. Complications of targeted drug therapies for solid malignancies: manifestations and mechanisms. AJR Am J Roentgenol, 200(3), 475-83, 2013.
Brewer, MR, Pao, W. Maximizing the benefits of off-target kinase inhibitor activity. Cancer Discov, 3(2), 138-40, 2013.
Jia, P, Jin, H, Meador, CB, Xia, J, Ohashi, K, Liu, L, Pirazzoli, V, Dahlman, KB, Politi, K, Michor, F, Zhao, Z, Pao, W. Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and -resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance. Genome Res, , , 2013.
Ohashi, K, Sequist, LV, Arcila, ME, Lovly, CM, Chen, X, Rudin, CM, Moran, T, Camidge, DR, Vnencak-Jones, CL, Berry, L, Pan, Y, Sasaki, H, Engelman, JA, Garon, EB, Dubinett, SM, Franklin, WA, Riely, GJ, Sos, ML, Kris, MG, Dias-Santagata, D, Ladanyi, M, Bunn, PA, Pao, W. Characteristics of Lung Cancers Harboring NRAS Mutations. Clin Cancer Res, 19(9), 2584-2591, 2013.
Yeh, P, Chen, H, Andrews, J, Naser, R, Pao, W, Horn, L. DNA-Mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT): a catalog of clinically relevant cancer mutations to enable genome-directed anticancer therapy. Clin Cancer Res, 19(7), 1894-901, 2013.
Dahlman, KB, Xia, J, Hutchinson, K, Ng, C, Hucks, D, Jia, P, Atefi, M, Su, Z, Branch, S, Lyle, P, Hicks, DJ, Bozon, V, Glaspy, JA, Rosen, N, Solit, DB, Netterville, JL, Vnencak-Jones, CL, Sosman, JA, Ribas, A, Zhao, Z, Pao, W. BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov, , , 2012.
Jia, P, Li, F, Xia, J, Chen, H, Ji, H, Pao, W, Zhao, Z. Consensus rules in variant detection from next-generation sequencing data. PLoS One, 7(6), e38470, 2012. PMCID:3371040
Levy, MA, Lovly, CM, Pao, W. Translating genomic information into clinical medicine: lung cancer as a paradigm. Genome Res, 22(11), 2101-8, 2012.
Lovly, CM, Dahlman, KB, Fohn, LE, Su, Z, Dias-Santagata, D, Hicks, DJ, Hucks, D, Berry, E, Terry, C, Duke, M, Su, Y, Sobolik-Delmaire, T, Richmond, A, Kelley, MC, Vnencak-Jones, CL, Iafrate, AJ, Sosman, J, Pao, W. Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One, 7(4), e35309, 2012. PMCID:3335021
Lovly, CM, Pao, W. Escaping ALK inhibition: mechanisms of and strategies to overcome resistance. Sci Transl Med, 4(120), 120ps2, 2012. PMCID:3335021
Ohashi, K, Sequist, LV, Arcila, ME, Moran, T, Chmielecki, J, Lin, YL, Pan, Y, Wang, L, de Stanchina, E, Shien, K, Aoe, K, Toyooka, S, Kiura, K, Fernandez-Cuesta, L, Fidias, P, Yang, JC, Miller, VA, Riely, GJ, Kris, MG, Engelman, JA, Vnencak-Jones, CL, Dias-Santagata, D, Ladanyi, M, Pao, W. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A, 109(31), E2127-33, 2012.
Pao, W. New approaches to targeted therapy in lung cancer. Proc Am Thorac Soc, 9(2), 72-3, 2012. PMCID:3371040
Takezawa, K, Pirazzoli, V, Arcila, ME, Nebhan, CA, Song, X, de Stanchina, E, Ohashi, K, Janjigian, YY, Spitzler, PJ, Melnick, MA, Riely, GJ, Kris, MG, Miller, VA, Ladanyi, M, Politi, K, Pao, W. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov, 2(10), 922-33, 2012.
Xia, J, Wang, Q, Jia, P, Wang, B, Pao, W, Zhao, Z. NGS catalog: A database of next generation sequencing studies in humans. Hum Mutat, 33(6), E2341-55, 2012. PMCID:3335021
Yatabe, Y, Pao, W, Jett, JR. Encouragement to Submit Data of Clinical Response to EGFR-TKIs in Patients With Uncommon EGFR Mutations. J Thorac Oncol, 7(5), 775-6, 2012.
Arcila, ME, Oxnard, GR, Nafa, K, Riely, GJ, Solomon, SB, Zakowski, MF, Kris, MG, Pao, W, Miller, VA, Ladanyi, M. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res, 17(5), 1169-80, 2011.
Garrett, JT, Olivares, MG, Rinehart, C, Granja-Ingram, ND, S?!nchez, V, Chakrabarty, A, Dave, B, Cook, RS, Pao, W, McKinely, E, Manning, HC, Chang, J, Arteaga, CL. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A, 108(12), 5021-6, 2011.
Janjigian, YY, Azzoli, CG, Krug, LM, Pereira, LK, Rizvi, NA, Pietanza, MC, Kris, MG, Ginsberg, MS, Pao, W, Miller, VA, Riely, GJ. Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res, 17(8), 2521-7, 2011.
Janjigian, YY, Park, BJ, Zakowski, MF, Ladanyi, M, Pao, W, D''Angelo, SP, Kris, MG, Shen, R, Zheng, J, Azzoli, CG. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol, 6(3), 569-75, 2011.
Johnson, ML, Riely, GJ, Rizvi, NA, Azzoli, CG, Kris, MG, Sima, CS, Ginsberg, MS, Pao, W, Miller, VA. Phase II Trial of Dasatinib for Patients with Acquired Resistance to Treatment with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Erlotinib or Gefitinib. J Thorac Oncol, 6(6), 1128-31, 2011.
Li, J, Su, Z, Ma, ZQ, Slebos, RJ, Halvey, P, Tabb, DL, Liebler, DC, Pao, W, Zhang, B. A bioinformatics workflow for variant Peptide detection in shotgun proteomics. Mol Cell Proteomics, 10(5), M110.006536, 2011.
Lovly, CM, Heuckmann, JM, de Stanchina, E, Chen, H, Thomas, RK, Liang, C, Pao, W. Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors. Cancer Res, , , 2011.
Ohashi, K, Pao, W. A new target for therapy in squamous cell carcinoma of the lung. Cancer Discov, 1(1), 23-4, 2011. PMCID:3371040
Oxnard, GR, Arcila, ME, Sima, CS, Riely, GJ, Chmielecki, J, Kris, MG, Pao, W, Ladanyi, M, Miller, VA. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res, 17(6), 1616-22, 2011.
Pao, W, Girard, N. New driver mutations in non-small-cell lung cancer. Lancet Oncol, 12(2), 175-80, 2011. PMCID:3064360
Pao, W, Iafrate, AJ, Su, Z. Genetically informed lung cancer medicine. J Pathol, 223(2), 230-40, 2011. PMCID:3070558
Rizvi, NA, Rusch, V, Pao, W, Chaft, JE, Ladanyi, M, Miller, VA, Krug, LM, Azzoli, CG, Bains, M, Downey, R, Flores, R, Park, B, Singh, B, Zakowski, M, Heelan, RT, Shen, R, Kris, MG. Molecular Characteristics Predict Clinical Outcomes: Prospective Trial Correlating Response to the EGFR Tyrosine Kinase Inhibitor Gefitinib with the Presence of Sensitizing Mutations in the Tyrosine Binding Domain of the EGFR Gene. Clin Cancer Res, 17(10), 3500-6, 2011.
Sengsayadeth, S, Montgomery, J, Pao, W. T4 or MI. J Thorac Oncol, 6(3), 632, 2011.
Su, Z, Dias-Santagata, D, Duke, M, Hutchinson, K, Lin, YL, Borger, DR, Chung, CH, Massion, PP, Vnencak-Jones, CL, Iafrate, AJ, Pao, W. A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer. J Mol Diagn, 13(1), 74-84, 2011.
Chmielecki, J, Peifer, M, Jia, P, Socci, ND, Hutchinson, K, Viale, A, Zhao, Z, Thomas, RK, Pao, W. Targeted next-generation sequencing of DNA regions proximal to a conserved GXGXXG signaling motif enables systematic discovery of tyrosine kinase fusions in cancer. Nucleic Acids Res, 38(20), 6985-96, 2010. PMCID:2978357
Clarke, JL, Pao, W, Wu, N, Miller, VA, Lassman, AB. High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer. J Neurooncol, 99(2), 283-6, 2010.
Gao, B, Sun, Y, Zhang, J, Ren, Y, Fang, R, Han, X, Shen, L, Liu, XY, Pao, W, Chen, H, Ji, H. Spectrum of LKB1, EGFR, and KRAS mutations in chinese lung adenocarcinomas. J Thorac Oncol, 5(8), 1130-5, 2010.
Girard, N, Deshpande, C, Azzoli, CG, Rusch, VW, Travis, WD, Ladanyi, M, Pao, W. Use of epidermal growth factor receptor/Kirsten rat sarcoma 2 viral oncogene homolog mutation testing to define clonal relationships among multiple lung adenocarcinomas: comparison with clinical guidelines. Chest, 137(1), 46-52, 2010. PMCID:2892178
Girard, N, Lou, E, Azzoli, CG, Reddy, R, Robson, M, Harlan, M, Orlow, I, Yatabe, Y, Nafa, K, Ladanyi, M, Viale, A, Kris, MG, Riely, G, Miller, V, Klein, RJ, Matsuo, K, Pao, W. Analysis of genetic variants in never-smokers with lung cancer facilitated by an Internet-based blood collection protocol: a preliminary report. Clin Cancer Res, 16(2), 755-63, 2010. PMCID:2808124
Jackman, D, Pao, W, Riely, GJ, Engelman, JA, Kris, MG, J??nne, PA, Lynch, T, Johnson, BE, Miller, VA. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol, 28(2), 357-60, 2010. PMCID:3072803
Pao, W, Chmielecki, J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer, 10(11), 760-74, 2010. PMCID:3072803
Pao, W, Iafrate, AJ, Su, Z. Genetically informed lung cancer medicine. J Pathol, , , 2010.
Price, KA, Azzoli, CG, Krug, LM, Pietanza, MC, Rizvi, NA, Pao, W, Kris, MG, Riely, GJ, Heelan, RT, Arcila, ME, Miller, VA. Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer. J Thorac Oncol, 5(10), 1623-9, 2010.
Redente, EF, Dwyer-Nield, LD, Merrick, DT, Raina, K, Agarwal, R, Pao, W, Rice, PL, Shroyer, KR, Malkinson, AM. Tumor progression stage and anatomical site regulate tumor-associated macrophage and bone marrow-derived monocyte polarization. Am J Pathol, 176(6), 2972-85, 2010. PMCID:2877857
Solomon, SB, Zakowski, MF, Pao, W, Thornton, RH, Ladanyi, M, Kris, MG, Rusch, VW, Rizvi, NA. Core needle lung biopsy specimens: adequacy for EGFR and KRAS mutational analysis. AJR Am J Roentgenol, 194(1), 266-9, 2010.
Sun, Y, Ren, Y, Fang, Z, Li, C, Fang, R, Gao, B, Han, X, Tian, W, Pao, W, Chen, H, Ji, H. Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J Clin Oncol, 28(30), 4616-20, 2010.
Sun, YH, Fang, R, Gao, B, Han, XK, Zhang, JH, Pao, W, Chen, HQ, Ji, HB. Comparable rate of EGFR kinase domain mutation in lung adenocarcinomas from Chinese male and female never-smokers. Acta Pharmacol Sin, 31(5), 647-8, 2010.
Veeriah, S, Taylor, BS, Meng, S, Fang, F, Yilmaz, E, Vivanco, I, Janakiraman, M, Schultz, N, Hanrahan, AJ, Pao, W, Ladanyi, M, Sander, C, Heguy, A, Holland, EC, Paty, PB, Mischel, PS, Liau, L, Cloughesy, TF, Mellinghoff, IK, Solit, DB, Chan, TA. Somatic mutations of the Parkinson''s disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet, 42(1), 77-82, 2010.
Weiss, J, Sos, ML, Seidel, D, Peifer, M, Zander, T, Heuckmann, JM, Ullrich, RT, Menon, R, Maier, S, Soltermann, A, Moch, H, Wagener, P, Fischer, F, Heynck, S, Koker, M, Sch??ttle, J, Leenders, F, Gabler, F, Dabow, I, Querings, S, Heukamp, LC, Balke-Want, H, Ans??n, S, Rauh, D, Baessmann, I, Altm??ller, J, Wainer, Z, Conron, M, Wright, G, Russell, P, Solomon, B, Brambilla, E, Brambilla, C, Lorimier, P, Sollberg, S, Brustugun, OT, Engel-Riedel, W, Ludwig, C, Petersen, I, S??nger, J, Clement, J, Groen, H, Timens, W, Sietsma, H, Thunnissen, E, Smit, E, Heideman, D, Cappuzzo, F, Ligorio, C, Damiani, S, Hallek, M, Beroukhim, R, Pao, W, Klebl, B, Baumann, M, Buettner, R, Ernestus, K, Stoelben, E, Wolf, J, N??rnberg, P, Perner, S, Thomas, RK. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med, 2(62), 62ra93, 2010.
Yeo, WL, Riely, GJ, Yeap, BY, Lau, MW, Warner, JL, Bodio, K, Huberman, MS, Kris, MG, Tenen, DG, Pao, W, Kobayashi, S, Costa, DB. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J Thorac Oncol, 5(7), 1048-53, 2010.
Zhao, B, Oxnard, GR, Moskowitz, CS, Kris, MG, Pao, W, Guo, P, Rusch, VM, Ladanyi, M, Rizvi, NA, Schwartz, LH. A pilot study of volume measurement as a method of tumor response evaluation to aid biomarker development. Clin Cancer Res, 16(18), 4647-53, 2010.
Girard N, Shen R, Guo T, Zakowski MF, Heguy A, Riely GJ, Huang J, Lau C, Lash AE, Ladanyi M, Viale A, Antonescu CR, Travis WD, Rusch VW, Kris MG, Pao W. . Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas.. Clinical Cancer Research, (15), 6790-6799, 2009.
Chitale D*, Gong Y*, Taylor BS*, Broderick S*, Brennan C, Somwar R, Golas B, Wang L, Motoi N, Szoke J, Reinersman JM, Major J, Sander C, Seshan VE, Zakowski MF, Rusch V, Pao W, Gerald W, Ladanyi M. . An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors.. Oncogene, (28), 2773-2783, 2009.
Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, Travis WD. . Comprehensive histologic assessment helps to differentiate multiple lung primary non-small cell carcinomas from metastases.. Am J Surg Pathol, (33), 1752-1764, 2009.
Girard N, Ostrovnaya I, Lau C, Park B, Ladanyi M, Finley D, Deshpande C, Rusch V, Orlow I, Travis WD, Pao W*, Begg CB*. . Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. . Clinical Cancer Research, (15), 5184-5190, 2009.
Gong Y, Yao E, Shen R, Goel A, Arcila M, Teruya-Feldstein J, Zakowski M, Frankel S, Peifer M, Thomas RK, Ladanyi M, and Pao W. . High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507). . PLoS One, (4), 7273, 2009.
Pao, W, Kris, MG, Iafrate, AJ, Ladanyi, M, J??nne, PA, Wistuba, II, Miake-Lye, R, Herbst, RS, Carbone, DP, Johnson, BE, Lynch, TJ. Integration of molecular profiling into the lung cancer clinic. Clin Cancer Res, 15(17), 5317-22, 2009. PMCID:3072803
Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, Koutcher JA, Spassove M, Ouerfelli O, Mellinghoff IK, Zakowski MF, Politi KA, Pao W. . Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. . J Clin Invest, (119), 3000-3010, 2009.
Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, St??ckrath I, Weiss J, Fischer F, Michel K, Goel A, Regales L, Politi KA, Perera S, Getlik M, Heukamp LC, Ans??n S, Zander T, Beroukhim R, Kashkar H, Shokat KM, Sellers WR, Rauh D, Orr C, Hoeflich KP, Friedman L, Wong KK, Pao W, Thomas RK. . Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. . Proc Natl Acad Scie USA, (106), 18351-18356, 2009.
Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, Michel K, Peifer M, Mermel C, Girard L, Peyton M, Gazdar A, Minna JD, Garraway LA, Kashkar H, Pao W, Meyerson M, Thomas RK. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.. Cancer Research, 69, 3256-3261, 2009.
Veeriah S, Brennan C, Meng S, Singh B, Fagin JA, Solit DB, Paty PB, Rohle D, Vivanco I, Chmielecki J, Pao W, Ladanyi M, Gerald WL, Liau L, Cloughesy TC, Mischel PS, Sander C, Taylor B, Schultz N, Major J, Heguy A, Fang F, Mellinghoff IK, Chan TA. . The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers. . Proc Natl Acad Sci USA, (106), 9435-9440, 2009.
Zakowski, MF, Hussain, S, Pao, W, Ladanyi, M, Ginsberg, MS, Heelan, R, Miller, VA, Rusch, VW, Kris, MG. Morphologic features of adenocarcinoma of the lung predictive of response to the epidermal growth factor receptor kinase inhibitors erlotinib and gefitinib. Arch Pathol Lab Med, 133(3), 470-7, 2009.
Azzoli, CG, Park, BJ, Pao, W, Zakowski, M, Kris, MG. Molecularly tailored adjuvant chemotherapy for resected non-small cell lung cancer: a time for excitement and equipoise. J Thorac Oncol, 3(1), 84-93, 2008.
Bean, J, Riely, GJ, Balak, M, Marks, JL, Ladanyi, M, Miller, VA, Pao, W. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res, 14(22), 7519-25, 2008. PMCID:2596620
Costa, DB, Nguyen, KS, Cho, BC, Sequist, LV, Jackman, DM, Riely, GJ, Yeap, BY, Halmos, B, Kim, JH, J??nne, PA, Huberman, MS, Pao, W, Tenen, DG, Kobayashi, S. Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib. Clin Cancer Res, 14(21), 7060-7, 2008. PMCID:2596582
Ladanyi, M, Pao, W. Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol, 21 Suppl 2, S16-22, 2008.
Li, AR, Chitale, D, Riely, GJ, Pao, W, Miller, VA, Zakowski, MF, Rusch, V, Kris, MG, Ladanyi, M. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn, 10(3), 242-8, 2008. PMCID:2329789
Lyustikman, Y, Momota, H, Pao, W, Holland, EC. Constitutive activation of Raf-1 induces glioma formation in mice. Neoplasia, 10(5), 501-10, 2008. PMCID:2373912
Marks, JL, Broderick, S, Zhou, Q, Chitale, D, Li, AR, Zakowski, MF, Kris, MG, Rusch, VW, Azzoli, CG, Seshan, VE, Ladanyi, M, Pao, W. Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma. J Thorac Oncol, 3(2), 111-6, 2008.
Marks, JL, Golas, B, Kirchoff, T, Miller, VA, Riely, GJ, Offit, K, Pao, W. EGFR mutant lung adenocarcinomas in patients with germline BRCA mutations. J Thorac Oncol, 3(7), 805, 2008.
Marks, JL, Gong, Y, Chitale, D, Golas, B, McLellan, MD, Kasai, Y, Ding, L, Mardis, ER, Wilson, RK, Solit, D, Levine, R, Michel, K, Thomas, RK, Rusch, VW, Ladanyi, M, Pao, W. Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res, 68(14), 5524-8, 2008. PMCID:2586155
Miller, VA, Riely, GJ, Zakowski, MF, Li, AR, Patel, JD, Heelan, RT, Kris, MG, Sandler, AB, Carbone, DP, Tsao, A, Herbst, RS, Heller, G, Ladanyi, M, Pao, W, Johnson, DH. Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. J Clin Oncol, 26(9), 1472-8, 2008.
Pratilas, CA, Hanrahan, AJ, Halilovic, E, Persaud, Y, Soh, J, Chitale, D, Shigematsu, H, Yamamoto, H, Sawai, A, Janakiraman, M, Taylor, BS, Pao, W, Toyooka, S, Ladanyi, M, Gazdar, A, Rosen, N, Solit, DB. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res, 68(22), 9375-83, 2008. PMCID:2649746
Riely, GJ, Kris, MG, Rosenbaum, D, Marks, J, Li, A, Chitale, DA, Nafa, K, Riedel, ER, Hsu, M, Pao, W, Miller, VA, Ladanyi, M. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res, 14(18), 5731-4, 2008. PMCID:2754127
Yang, CH, Yu, CJ, Shih, JY, Chang, YC, Hu, FC, Tsai, MC, Chen, KY, Lin, ZZ, Huang, CJ, Shun, CT, Huang, CL, Bean, J, Cheng, AL, Pao, W, Yang, PC. Specific EGFR mutations predict treatment outcome of stage IIIB/IV patients with chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib monotherapy. J Clin Oncol, 26(16), 2745-53, 2008.
Bean, J, Brennan, C, Shih, JY, Riely, G, Viale, A, Wang, L, Chitale, D, Motoi, N, Szoke, J, Broderick, S, Balak, M, Chang, WC, Yu, CJ, Gazdar, A, Pass, H, Rusch, V, Gerald, W, Huang, SF, Yang, PC, Miller, V, Ladanyi, M, Yang, CH, Pao, W. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A, 104(52), 20932-7, 2007. PMCID:2409244
Gao, SP, Mark, KG, Leslie, K, Pao, W, Motoi, N, Gerald, WL, Travis, WD, Bornmann, W, Veach, D, Clarkson, B, Bromberg, JF. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest, 117(12), 3846-56, 2007. PMCID:2096430
Gong, Y, Somwar, R, Politi, K, Balak, M, Chmielecki, J, Jiang, X, Pao, W. Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med, 4(10), e294, 2007. PMCID:2001209
Marks, JL, McLellan, MD, Zakowski, MF, Lash, AE, Kasai, Y, Broderick, S, Sarkaria, IS, Pham, D, Singh, B, Miner, TL, Fewell, GA, Fulton, LL, Mardis, ER, Wilson, RK, Kris, MG, Rusch, VW, Varmus, H, Pao, W. Mutational analysis of EGFR and related signaling pathway genes in lung Adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4. PLoS ONE, 2(5), e426, 2007. PMCID:1855985
Milton, DT, Riely, GJ, Azzoli, CG, Gomez, JE, Heelan, RT, Kris, MG, Krug, LM, Pao, W, Pizzo, B, Rizvi, NA, Miller, VA. Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer, 110(3), 599-605, 2007.
Pao, W, Ladanyi, M. Epidermal growth factor receptor mutation testing in lung cancer: searching for the ideal method. Clin Cancer Res, 13(17), 4954-5, 2007.
Regales, L, Balak, MN, Gong, Y, Politi, K, Sawai, A, Le, C, Koutcher, JA, Solit, DB, Rosen, N, Zakowski, MF, Pao, W. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS ONE, 2(8), e810, 2007. PMCID:1950079
Riely, GJ, Kris, MG, Zhao, B, Akhurst, T, Milton, DT, Moore, E, Tyson, L, Pao, W, Rizvi, NA, Schwartz, LH, Miller, VA. Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res, 13(17), 5150-5, 2007.
Weir, BA, Woo, MS, Getz, G, Perner, S, Ding, L, Beroukhim, R, Lin, WM, Province, MA, Kraja, A, Johnson, LA, Shah, K, Sato, M, Thomas, RK, Barletta, JA, Borecki, IB, Broderick, S, Chang, AC, Chiang, DY, Chirieac, LR, Cho, J, Fujii, Y, Gazdar, AF, Giordano, T, Greulich, H, Hanna, M, Johnson, BE, Kris, MG, Lash, A, Lin, L, Lindeman, N, Mardis, ER, McPherson, JD, Minna, JD, Morgan, MB, Nadel, M, Orringer, MB, Osborne, JR, Ozenberger, B, Ramos, AH, Robinson, J, Roth, JA, Rusch, V, Sasaki, H, Shepherd, F, Sougnez, C, Spitz, MR, Tsao, MS, Twomey, D, Verhaak, RG, Weinstock, GM, Wheeler, DA, Winckler, W, Yoshizawa, A, Yu, S, Zakowski, MF, Zhang, Q, Beer, DG, Wistuba, II, Watson, MA, Garraway, LA, Ladanyi, M, Travis, WD, Pao, W, Rubin, MA, Gabriel, SB, Gibbs, RA, Varmus, HE, Wilson, RK, Lander, ES, Meyerson, M. Characterizing the cancer genome in lung adenocarcinoma. Nature, 450(7171), 893-8, 2007. PMCID:2538683
Balak, MN, Gong, Y, Riely, GJ, Somwar, R, Li, AR, Zakowski, MF, Chiang, A, Yang, G, Ouerfelli, O, Kris, MG, Ladanyi, M, Miller, VA, Pao, W. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res, 12(21), 6494-501, 2006.
Christiani, DC, Pao, W, DeMartini, JC, Linnoila, RI, Malkinson, AM, Onn, A, Politi, KA, Sharp, M, Wong, KK, Kim, K. BAC consensus conference, November 4-6, 2004: epidemiology, pathogenesis, and preclinical models. J Thorac Oncol, 1(9 Suppl), S2-7, 2006.
Milton, DT, Azzoli, CG, Heelan, RT, Venkatraman, E, Gomez, JE, Kris, MG, Krug, LM, Pao, W, Rizvi, NA, Dunne, M, Miller, VA. A phase I/II study of weekly high-dose erlotinib in previously treated patients with nonsmall cell lung cancer. Cancer, 107(5), 1034-41, 2006.
Milton, DT, Riely, GJ, Pao, W, Miller, VA, Kris, MG, Heelan, RT. Molecular on/off switch. J Clin Oncol, 24(30), 4940-2, 2006.
Pao, W. Defining clinically relevant molecular subsets of lung cancer. Cancer Chemother Pharmacol, 58 Suppl 1, s11-5, 2006.
Pao, W. Monitoring EGFR-mutant lung cancers by means of the blood. J Thorac Oncol, 1(3), 199-200, 2006.
Pham, D, Kris, MG, Riely, GJ, Sarkaria, IS, McDonough, T, Chuai, S, Venkatraman, ES, Miller, VA, Ladanyi, M, Pao, W, Wilson, RK, Singh, B, Rusch, VW. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol, 24(11), 1700-4, 2006.
Politi, K, Zakowski, MF, Fan, PD, Schonfeld, EA, Pao, W, Varmus, HE. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev, 20(11), 1496-510, 2006. PMCID:1475762
Riely, GJ, Pao, W, Pham, D, Li, AR, Rizvi, N, Venkatraman, ES, Zakowski, MF, Kris, MG, Ladanyi, M, Miller, VA. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res, 12(3 Pt 1), 839-44, 2006.
Riely, GJ, Politi, KA, Miller, VA, Pao, W. Update on epidermal growth factor receptor mutations in non-small cell lung cancer. Clin Cancer Res, 12(24), 7232-41, 2006.
Carter, TA, Wodicka, LM, Shah, NP, Velasco, AM, Fabian, MA, Treiber, DK, Milanov, ZV, Atteridge, CE, Biggs, WH, Edeen, PT, Floyd, M, Ford, JM, Grotzfeld, RM, Herrgard, S, Insko, DE, Mehta, SA, Patel, HK, Pao, W, Sawyers, CL, Varmus, H, Zarrinkar, PP, Lockhart, DJ. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A, 102(31), 11011-6, 2005. PMCID:1180625
Lassman, AB, Rossi, MR, Raizer, JJ, Razier, JR, Abrey, LE, Lieberman, FS, Grefe, CN, Lamborn, K, Pao, W, Shih, AH, Kuhn, JG, Wilson, R, Nowak, NJ, Cowell, JK, DeAngelis, LM, Wen, P, Gilbert, MR, Chang, S, Yung, WA, Prados, M, Holland, EC. Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors: tissue analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01. Clin Cancer Res, 11(21), 7841-50, 2005.
Pan, Q, Pao, W, Ladanyi, M. Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. J Mol Diagn, 7(3), 396-403, 2005. PMCID:1867537
Pao, W, Ladanyi, M, Miller, VA, , . Erlotinib in lung cancer. N Engl J Med, 353(16), 1739-41; author reply 1739-41, 2005.
Pao, W, Miller, VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol, 23(11), 2556-68, 2005.
Pao, W, Miller, VA, Politi, KA, Riely, GJ, Somwar, R, Zakowski, MF, Kris, MG, Varmus, H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med, 2(3), e73, 2005. PMCID:549606
Pao, W, Wang, TY, Riely, GJ, Miller, VA, Pan, Q, Ladanyi, M, Zakowski, MF, Heelan, RT, Kris, MG, Varmus, HE. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med, 2(1), e17, 2005. PMCID:545207
Ren, GP, Wang, TY, Pan, QL, Pao, W, Huai, J. Epidermal growth factor receptor mutations detected in tumors from Chinese "never smokers" with lung adenocarcinoma. Chin Med J (Engl), 118(9), 769-71, 2005.
Riely, GJ, Pao, W. Combining EGFR targeted therapy with chemotherapy in pancreatic cancer: is timing important. Cancer Biol Ther, 4(10), 1096-7, 2005.
Shah, NT, Kris, MG, Pao, W, Tyson, LB, Pizzo, BM, Heinemann, MH, Ben-Porat, L, Sachs, DL, Heelan, RT, Miller, VA. Practical management of patients with non-small-cell lung cancer treated with gefitinib. J Clin Oncol, 23(1), 165-74, 2005.
Varmus, H, Pao, W, Politi, K, Podsypanina, K, Du, YC. Oncogenes come of age. Cold Spring Harb Symp Quant Biol, 70, 1-9, 2005. PMCID:1791364
Miller, VA, Kris, MG, Shah, N, Patel, J, Azzoli, C, Gomez, J, Krug, LM, Pao, W, Rizvi, N, Pizzo, B, Tyson, L, Venkatraman, E, Ben-Porat, L, Memoli, N, Zakowski, M, Rusch, V, Heelan, RT. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol, 22(6), 1103-9, 2004.
Pao, W, Miller, V, Zakowski, M, Doherty, J, Politi, K, Sarkaria, I, Singh, B, Heelan, R, Rusch, V, Fulton, L, Mardis, E, Kupfer, D, Wilson, R, Kris, M, Varmus, H. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A, 101(36), 13306-11, 2004. PMCID:516528
Pao, W, Miller, VA, Kris, MG. ''Targeting'' the epidermal growth factor receptor tyrosine kinase with gefitinib (Iressa) in non-small cell lung cancer (NSCLC). Semin Cancer Biol, 14(1), 33-40, 2004.
Pao, W, Miller, VA, Venkatraman, E, Kris, MG. Predicting sensitivity of non-small-cell lung cancer to gefitinib: is there a role for P-Akt. J Natl Cancer Inst, 96(15), 1117-9, 2004.
Cong, F, Zhang, J, Pao, W, Zhou, P, Varmus, H. A protein knockdown strategy to study the function of beta-catenin in tumorigenesis. BMC Mol Biol, 4, 10, 2003. PMCID:222962
Pao, W, Klimstra, DS, Fisher, GH, Varmus, HE. Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance. Proc Natl Acad Sci U S A, 100(15), 8764-9, 2003. PMCID:166387
Zhang, F, Pao, W, Umphress, SM, Jakowlew, SB, Meyer, AM, Dwyer-Nield, LD, Nielsen, LD, Takeda, K, Gelfand, EW, Fisher, JH, Zhang, L, Malkinson, AM, Mason, RJ. Serum levels of surfactant protein D are increased in mice with lung tumors. Cancer Res, 63(18), 5889-94, 2003.
Girard N, Ostrovnaya I, Lau C, Park B, Ladanyi M, Finley D, Deshpande C, Rusch V, Orlow I, Travis WD, Pao W*, Begg CB*. . Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers. . Clinical Cancer Research, (15), 5184-5190, 2001.
Khan, KM, Pao, W, Kendler, J. Epidural abscess and vertebral osteomyelitis caused by Listeria monocytogenes: case report and literature review. Scand J Infect Dis, 33(9), 714-6, 2001.
Pao, W, Duncan, KO, Bolognia, JL, Carroll, CB, Hotez, PJ, Bessen, DE. Numerous eruptive lesions of panniculitis associated with group A streptococcus bacteremia in an immunocompetent child. Clin Infect Dis, 27(3), 430-3, 1998.
Wen, L, Barber, DF, Pao, W, Wong, FS, Owen, MJ, Hayday, A. Primary gamma delta cell clones can be defined phenotypically and functionally as Th1/Th2 cells and illustrate the association of CD4 with Th2 differentiation. J Immunol, 160(4), 1965-74, 1998.
Passoni, L, Hoffman, ES, Kim, S, Crompton, T, Pao, W, Dong, MQ, Owen, MJ, Hayday, AC. Intrathymic delta selection events in gammadelta cell development. Immunity, 7(1), 83-95, 1997.
Dianda, L, Gulbranson-Judge, A, Pao, W, Hayday, AC, MacLennan, IC, Owen, MJ. Germinal center formation in mice lacking alpha beta T cells. Eur J Immunol, 26(7), 1603-7, 1996.
Mallick-Wood, CA, Pao, W, Cheng, AM, Lewis, JM, Kulkarni, S, Bolen, JB, Rowley, B, Tigelaar, RE, Pawson, T, Hayday, AC. Disruption of epithelial gamma delta T cell repertoires by mutation of the Syk tyrosine kinase. Proc Natl Acad Sci U S A, 93(18), 9704-9, 1996. PMCID:38493
Pao, W, Wen, L, Smith, AL, Gulbranson-Judge, A, Zheng, B, Kelsoe, G, MacLennan, IC, Owen, MJ, Hayday, AC. Gamma delta T cell help of B cells is induced by repeated parasitic infection, in the absence of other T cells. Curr Biol, 6(10), 1317-25, 1996.
Wen, L, Pao, W, Wong, FS, Peng, Q, Craft, J, Zheng, B, Kelsoe, G, Dianda, L, Owen, MJ, Hayday, AC. Germinal center formation, immunoglobulin class switching, and autoantibody production driven by "non alpha/beta" T cells. J Exp Med, 183(5), 2271-82, 1996. PMCID:2192585
Cheng, AM, Rowley, B, Pao, W, Hayday, A, Bolen, JB, Pawson, T. Syk tyrosine kinase required for mouse viability and B-cell development. Nature, 378(6554), 303-6, 1995.
Kyes, S, Pao, W, Hayday, A. Influence of site of expression on the fetal gamma delta T-cell receptor repertoire. Proc Natl Acad Sci U S A, 88(17), 7830-3, 1991. PMCID:52397
A postdoctoral position is immediately available to investigate mechanisms of lung tumorigenesis, with particular emphasis on mechanisms of sensitivity and resistance to targeted therapies in human lung cancer, utilizing various molecular techniques, human specimens, and mouse models. Applicants should be highly motivated individuals who have a PhD and/or MD degree, extensive background in molecular biology, and interest in cancer biology. Knowledge in working with xenografts and transgenic mouse models is a plus. Fellow will be part of a strong collaborative and multidisciplinary research team. Please send curriculum vitae and names of references to: William Pao, MD, PhD, E-mail: firstname.lastname@example.org.