Browse by Medical Category
Research at Mass General
Jeffrey A. Engelman, MD, PhD
Director, Center for Thoracic Oncology and Molecular TherapeuticsMassachusetts General Hospital Cancer Center
Laurel Schwartz Associate Professor of MedicineHarvard Medical School
The research goal of the Engelman laboratory is to advance targeted therapies to beneﬁt patients with cancer. Our research focuses on understanding the biological underpinnings of sensitivity and resistance to speciﬁc kinase inhibitor targeted therapies in cancers with speciﬁc genetic abnormalities. In particular, we focus on the regulation of key signaling networks that regulate cancer cell growth and survival. We study how perturbation of speciﬁc signaling pathways (alone or in combination) impairs cell growth and induces cell death. More recently, our research has also begun to focus on how one should model responsiveness to therapies in the laboratory to optimally inform what will occur in the clinic. Our studies combine cell culture models, mouse models, and assessment of clinical specimens. Our laboratory focuses on both established targeted paradigms such as EGFR and ALK mutant lung cancers, as well as cancers for which no effective targeted therapy currently exists, such as PI3K mutant breast cancers and KRAS mutant lung cancers.
Jeffrey A. Engelman, MD, PhDPrincipal Investigator
EGFR inhibitors have revolutionized the treatment of EGFR mutant lung cancer, with patients achieving robust responses. However, relapse typically occurs after one year of treatment. The implementation of repeat biopsy programs at the time of resistance has been instrumental in understanding the molecular mechanisms underlying acquired resistance to ﬁrst-generation EGFR tyrosine kinase inhibitors (TKIs). By analyzing biopsy specimens, we have identiﬁed a number of resistance mechanisms, all of which confer resistance to TKI via reactivation of key downstream signaling pathways. Third-generation EGFR inhibitors have recently entered clinical testing and we are exploring their ability to re-sensitize resistant cancers.
Anaplastic lymphoma kinase (ALK) gene rearrangements have emerged as well-established oncogenic drivers and therapeutic targets in non–small cell lung cancer (NSCLC). Lung cancers with ALK rearrangements are highly sensitive to crizotinib, an ALK tyrosine kinase inhibitor, underscoring the notion that such cancers are addicted to ALK kinase activity. However, despite a high initial response rate, most patients develop resistance to crizotinib within 2 years. Many molecular mechanisms of resistance to crizotinib have been identiﬁed. Ceritinib has recently entered the clinic for treatment of ALK-positive NSCLC patients. Our work interrogating both in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations.
The phosphatidylinositol 3-kinase (PI3K) pathway is a key regulator of growth, survival, and metabolism in both normal and malignant cells. With over 70% of breast cancers harboring activation of the PI3K pathway, a number of PI3K inhibitors have entered clinical trials. However, results of single-agent PI3K inhibitors have been modest to date. We have determined that the initial efficacy of BYL719 (a p110αspeciﬁc inhibitor) is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110βisoform. Consistently, we have shown that the addition of a p110βinhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-ampliﬁed and PIK3CA mutant cancers.
KRAS is the most common driver oncogene in lung cancer and development of therapeutic strategies to improve the survival of these patients represents one of the most important needs in all of oncology. Two major treatment modalities that have profoundly altered the treatment paradigm for patients with lung cancer are targeted therapies and, more recently, immunotherapy. We are interested in understanding how targeted therapies and immunotherapies can be optimized and integrated in order to radically improve the outcomes of patients with KRAS mutant lung cancer. We believe this approach will set a new standard for understanding how interactions between oncoprotein-activated pathways and the immune microenvironment regulate tumor growth.
View a list of publications by researchers at the Engelman Laboratory
Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR, Katayama R, Costa C, Ross KN, Moran T, Howe E, Fulton LE, Mulvey HE, Bernardo LA, Mohamoud F, Miyoshi N, VanderLaan PA, Costa DB, Jänne PA, Borger DR, Ramaswamy S, Shioda T, Iafrate AJ, Getz G, Rudin CM, Mino-Kenudson M, Engelman JA. RB loss in resistant EGFR mutant lung adenocarci-nomas that transform to small-cell lung cancer. Nature Communications. (2015). Mar 11;6:6377.
Crystal AS, Shaw AT, Sequist LV, Fribou-let L, Niederst MJ, Lockerman EL, Frias RL, Gainor JF, Amzallag A, Greninger P, Lee D, Kalsy A, Gomez-Caraballo M, Elamine L, Howe E, Hur W, Lifshits E, Robinson HE, Katayama R, Faber AC, Awad MM, Ramaswamy S, Mino-Kenudson M, Iafrate AJ, Benes CH, Engelman JA. Patient-derived models of acquired resistance can identify effec-tive drug combinations for cancer. Science. (2014). Dec 19;346(6216):1480-6.
Shaw AT, Kim DW, Mehra R, Tan DW, Felip E, Chow LQ, Camidge R, Vansteen-kiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwas-ser M, Boral AL, Engelman JA. Ceritinib in ALK-Rearranged Non–Small Cell Lung Cancer. New England Journal of Medicine. (2014) Mar 27;370(13):1189-97.
Vora SR, Juric D, Kim N, Mino-Kenud-son M, Huynh T, Costa C1, Lockerman EL, Pollack SF, Liu M, Li X, Lehar J, Wiesmann M, Wartmann M, Chen Y, Cao ZA, Pinzon-Ortiz M, Kim S, Schlegel R, Huang A, Engelman JA. CDK 4/6 Inhibitors Sensitize PIK3CA Mutant Breast Cancer to PI3K Inhibitors. Cancer Cell. (2014 ). Jul 14;26(1):136-49.
Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA. Synthetic Lethal In-teraction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models. Cancer Cell. (2013). Jan 14;23(1):121-8.
Back to Top