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Laboratory-based investigations of Targeted Therapies in Lung Cancer Our laboratory work focuses on studying preclinical models of lung cancers that harbor oncogenic alterations. The main focus of our work is to understand how oncogenic alterations found in lung cancer lead to sensitivity of targeted therapies. Furthermore, we extensively study both model systems and patient derived tumors to uncover mechanisms of drug resistance. Through these studies we have been able to identify novel therapeutic strategies for patients with different genomic subtypes of lung cancer.

Preclinical and clinical development of novel EGFR directed therapies The most common mechanism (found in 60% of patients) of resistance to EGFR inhibitors is the secondary EGFR T790M mutation. The initial studies identified a second class of EGFR inhibitors, covalent or irreversible inhibitors, which could still be effective in model systems harboring EGFR T790M. We have extensively studied one such covalent inhibitor, dacomitinib, both in preclinical models and in lung cancer patients and despite its efficacy in preclinical models, this drug was not clinically effective in EGFR mutant lung cancer patients that had failed first generation inhibitors. One reason for this disconnect pre-clinically and clinically is that the concentrations of dacomitinib required to inhibit EGFR T790M cannot be reached in patients due to the development of on-target dose limiting toxicity (skin rash, mediated by inhibition of wild type (WT) EGFR) at much lower doses. Prompted by these clinical observations, we began working together with Dr. Nathanael Gray (who is a kinase chemist at DFCI) to tackle this problem. These studies led us to identify a previously unknown class of covalent inhibitors, irreversible pyrimidine inhibitors, which were effective EGFR inhibitors This novel chemical class of agents is both more potent than irreversible quinazolines (like dacomitinib) against EGFR T790M and is EGFR wild type sparing thus potentially improving the therapeutic window. At least 7 pharmaceutical companies have now developed clinical agents inspired by our original finding. We led the phase I clinical trial of one of these agents, osimertinib (AZD9291), which was approved by the FDA in November 2015. We continue to study this class of inhibitors and to use both laboratory and clinical studies to develop novel combination therapies.  

Clinical trials of targeted therapies in lung cancer Dr. Jänne has led multiple clinical trials of targeted therapies for patients with specific genomic subtypes of lung cancer. Many of these studies have led to either changing or improving the standard of care for patients with lung cancer. Currently, Dr. Jänne is focusing on developing combination targeted therapies and on clinical studies focusing on preventing and/delaying the emergence of drug resistance.

Paez, J.G., *Jänne, P.A., Lee, J.C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F.J., Lindeman, N. Boggon, T.J., Naoki, K., Sasaki, H., Fujii, Y., Eck, M.J., Sellers, W.R., Johnson, B.E., and Meyerson, M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304 (5676):1497-1500. * co-first author

Jackman, D.M., Yeap, B.Y., Lindeman, N.I., Fidias, P., Rabin, M.S., Temel, J., Skarin, A.T., Meyerson, M., Holmes, A.J., Borras, A.M., Friedlin, B., Ostler, P.A. ,Lucca, J., Lynch, T.J., Johnson, B.E. and Jänne, P.A., .A phase II study of chemotherapy-naïve patients > 70 years of age treated with erlotinib for advanced non-small cell lung cancer. J Clin Oncol 2007; 25(7):760-6

Jänne, P.A., Wang, X., Socinski, M.A., Crawford, J., Stinchcombe, T.E., Gu, L. Capelletti, M., Edelman, M.J., Villalona-Calero, M.A., Kratzke, R., Vokes, E.E. and Miller, V.A. A randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light   former smokers with advanced lung adenocarcinoma: Cancer and Leukemia Group B trial 30406. Journal of Clinical Oncology 2012; 30(17):2063-9.

Jänne, P.A., Ou, S.-H. I., Kim, D.-W., Oxnard, G.R., Martins, R., Kris, M.G., Dunphy, F., Nishio, M., O’Connell, J., Paweletz, C., Taylor, I., Zhang, H., Goldberg, Z., and Mok, T. Phase 2 trial of dacomitinib as initial treatment in patients with clinically and/or molecularly selected advanced non-   small cell lung cancer. Lancet Oncol 2014; (13):1433-41.

Engelman, J.A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J.O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., Kosaka, K., Holmes, A.J., Rogers, A.M., Cappuzzo, F., Mok, T., Lee, C., Johnson, B.E., Cantley, L.C., Jänne, P.A. MET Amplification Leads to Gefitinib Resistance by Activating ERBB3 Signaling in Lung Cancer. Science 2007; 316(5827):1039-43

Turke, A.,B., Zejnullahu, K., Wu, Y.-L., Song, Y., Dias-Santagata, D., Lifshits, E., Toschi, L., Rogers, A., Mok, T., Sequist, L., Lindeman, N.I., Murphy, c., Akhavanfard, S., Yeap, B.Y., Xiao, Y., Capelletti, M., Iafrate, A.J., Lee, C., Christensen, J.G., Engelman, J.A., and Jänne, P.A. Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010; 17(1):77-88

Yonesaka, K., Zejnullahu, K., Okamoto, I., Satoh, T., Cappuzzo, F., Souglakos, J., Ercan, D., Rogers, A., Roncalli, M., Takeda, M., Fujisaka, Y., Philips, J., Shimizu, T., Maenishi, O., Cho, Y., Sun, J., Destro, A., Taira, K., Takeda, K., Okabe, T., Swanson, J., Itoh, H., Takada, M., Lifshits, E., Okuno, K., Engelman, J.A., Shivdasani, R.A., Nishio, K., Fukuoka, M., Varella-Garcia, M., Nakagawa, K. and Jänne, P.A. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Science Translational Medicine 2011; 3(99):99ra86

Sasaki, T., Koivunen, J., Ogino, A., Yanagita, M., Nikiforow, S., Zheng, W., Lathan, C., Marcoux, J.P., Du, J., Okuda, K., Capelletti, M., Shimamura, T., Ercan, D., Stumpfova, M., Xiao, Y., Weremowicz, S., Butaney, M., Heon, S., Wilner, K., Christensen, J.G., Eck, M.J., Wong, K.-K., Lindeman, N., Gray, N.S., Rodig, S.J., and Jänne, P.A. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Research 2011; 71(18):6051-60.

Engelman, J.A., Zejnullahu, K, Gale, C.-M., Lifshits, E., Gonzales, A.J., Shimamura, T., Zhao, F., Vincent, P.W., Naumov, G.N., Bradner, J.E., Althaus, I.W., Gandhi, L., Shapiro, G.I., Nelson, J.M., Heymach, J.V., Meyerson, M., Wong, K.-K. and Jänne, P.A. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Research 2007; 67:11924-32.

Jänne P.A., Boss D.S., Camidge D.R., Britten C.D., Engelman J.A., Garon E.B., Guo F., Wong S., Liang J., Letrent S., Millham R., Taylor I., Eckhardt S.G., and Schellens J.H. Phase I dose- escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011 Mar 1;17(5):1131-9.

Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A.B., chirieac, L., Iacob, R.E., Padera, R., Engen, J.R., Wong, K.-K., Eck, M.J., Gray, N.S., and Jänne, P.A. Novel mutant selective EGFR kinase inhibitors effective against EGFR T790M. Nature 2009; 462(7276):1070-4

Jänne, P.A., Yang, J.C.-H., Kim, D.-W., Planchard, D., Ohe, Y., Ramalingam, S.S., Ahn, M.-J., Kim, S.-W., Su, W.-C., M.D., Horn, L., Haggstrom, D., Felip, E., Kim, J.-H., Frewer, P., Cantarini, M., Brown, K.H., Dickinson, Ghiorghiu, G., and Ranson, M. AZD9291 in EGFR Inhibitor Resistant Non-Small Cell Lung Cancer. New England Journal of Medicine, 2015; 372(18):1689-99

Lipson D., Capelletti M., Yelensky R., Otto G., Parker A., Jarosz M., Curran J.A., Balasubramanian S., Bloom T., Brennan K.W., Donahue A., Downing S.R., Frampton G.M., Garcia L., Juhn F., Mitchell K.C., White E., White J., Zwirko Z., Peretz T., Nechushtan H., Soussan-Gutman L., Kim J., Sasaki H., Kim H.R., Park S.I., Ercan D., Sheehan C.E., Ross J.S., Cronin M.T., Jänne P.A*., and Stephens P.J. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012 Feb 12;18(3):382-4 *co-senior author

Vaishnavi A., Capelletti M., Le A.T., Kako S., Butaney M., Ercan D., Mahale S., Davies K.D., Aisner D.L., Pilling A.B., Berge E.M., Kim J., Sasaki H., Park S.I., Kryukov G., Garraway L.A., Hammerman P.S., Haas J., Andrews S.W., Lipson D., Stephens P.J., Miller V.A., Varella-Garcia M., *Jänne P.A., and Doebele R.C. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469-72. *co-senior author

Shaw, A.T., Kim, D.-W., Nakagawa, K., Seto, T., Crino, L., Ahn, M.-J., De Pas, T., Besse, B., Solomon, B.J., Blackhall, F., Wu, Y.-L., Thomas, M., O’Byrne, K.J., Moro-Sibilot, D., Camidge, D.R., Mok, T., Hirsch, V., Riely, G.J., Iyer, S., Tassell, V., Polli, A., Wilner, K.D., and Jänne, P.A., Crizotinib versus Chemotherapy in Advanced ALK-rearranged Lung Cancer. New England Journal of Medicine, 2013; 368(25):2385-94

Jänne, P.A., Shaw, A.T., Pereira, J.R., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F.A., Grinsted, L., Zazulina, V., Smith, P., Smith, I. and Crino, L. Selumetinib plus docetaxel for KRAS- mutant advanced non-small cell lung cancer: a randomised, multicentre, phase 2 study. Lancet Oncology 2013; 14(1):38-47