Photo of Ryan B Corcoran,  MD, PhD

Ryan B Corcoran, MD, PhD

Massachusetts General Hospital

Massachusetts General Hospital


rbcorcoran@partners.org

Ryan B Corcoran, MD, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Assistant Professor, Medicine, Harvard Medical School
  • Assistant Professor, Cancer Center, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

As a gastrointestinal oncologist with a primary interest in translational oncology research, my work focuses on targeted therapies directed against specific mutations commonly found in human cancers, with a focus on BRAF and KRAS mutant gastrointestinal cancers. My work explores the hypothesis that the optimal therapy for individual tumors may vary widely based on the genetic alterations present, and that prior knowledge of these genetic changes and an understanding of the signaling pathways involved will allow selection of an optimal targeted agent or combination of agents capable of inhibiting the critical survival signals within a given tumor.

My work on BRAF mutant cancers has focused on determinants of resistance to BRAF and MEK inhibitors. We have identified BRAF amplification as a potential cause of acquired and de novo resistance in BRAF mutant colorectal cancers (Science Signaling, 2010), and have shown that combined BRAF and MEK inhibition can overcome resistance. We have also demonstrated that combined BRAF and MEK inhibition leads to increased efficacy in treatment-naïve BRAF mutant colorectal cancer models, leading to the development of a clinical trial assessing combined BRAF and MEK inhibition in patients with BRAF mutant colorectal (ASCO Abstract, 2012; ASCO Abstract, 2013). Additionally, we have found that EGFR-mediated reactivation of MAPK signaling contributes to the relative insensitivity of BRAF mutant colorectal cancers to BRAF inhibition, compared to BRAF mutant melanomas, and that combined BRAF and EGFR inhibition can overcome resistance, leading to tumor regressions in BRAF mutant colorectal xenografts (Cancer Discovery, 2012). Clinical trials based on this concept are currently enrolling patients. We are also focused on identifying additional causes of de novo and acquired resistance in BRAF mutant cancers using a combination of preclinical models and patient tumor specimens. (Cancer Discovery, 2015). Simultaneously, we are developing biomarkers to predict response to therapy (Cancer Discovery, 2011), including real-time pharmacodynamic assessment of signaling changes in on-treatment patient tumor biopsies (Science Translational Medicine, 2013), and combination therapy strategies to overcome resistance.

In KRAS mutant cancers, we have demonstrated the effectiveness of combination therapies involving inhibition of the PI3K and MEK pathways in mouse models of KRAS mutant cancers (J Clinical Investigation, 2011) and have evaluated the role of STAT3 in KRAS-induced pancreatic tumorigenesis (Cancer Research, 2011). Our current work focuses on identifying new combination therapy approaches to KRAS mutant cancers in an effort to identify novel target pathways. Recently, we identified combined targeting of BCL-XL and MEK as a promising therapeutic strategy that leads to dramatic tumor regressions in KRAS mutant xenografts and in KRAS-driven genetically-engineered mouse tumor models (Cancer Cell, 2013). A clinical trial based on this concept and funded by NCI/CTEP is currently enrolling patients, for which I am principal investigator. By identifying and understanding key mechanisms of response and resistance to targeted therapies, we hope to devise and validate potential clinical strategies for BRAF and KRAS mutant cancers.

Publications

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  • Ahronian LG, Corcoran RB. Strategies for monitoring and combating resistance to combination kinase inhibitors for cancer therapy. Genome Med 2017; 9:37. PubMed
  • Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, Lennerz JK, Vu P, Deshpande V, Kambadakone A, Mussolin B, Reyes S, Henderson L, Sun JE, Van Seventer EE, Gurski JM, Baltschukat S, Schacher-Engstler B, Barys L, Stamm C, Furet P, Ryan DP, Stone JR, Iafrate AJ, Getz G, Porta DG, Tiedt R, Bardelli A, Juric D, Corcoran RB, Bardeesy N, Zhu AX. Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion-Positive Cholangiocarcinoma. 2016. PubMed
  • Manchado E, Weissmueller S, Morris JP, Chen CC, Wullenkord R, Lujambio A, de Stanchina E, Poirier JT, Gainor JF, Corcoran RB, Engelman JA, Rudin CM, Rosen N, Lowe SW. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 2016; 534:647-51. PubMed
  • Oddo D, Sennott EM, Barault L, Valtorta E, Arena S, Cassingena A, Filiciotto G, Marzolla G, Elez E, van Geel RM, Bartolini A, Crisafulli G, Boscaro V, Godfrey JT, Buscarino M, Cancelliere C, Linnebacher M, Corti G, Truini M, Siravegna G, Grasselli J, Gallicchio M, Bernards R, Schellens JH, Tabernero J, Engelman JA, Sartore-Bianchi A, Bardelli A, Siena S, Corcoran RB, Di Nicolantonio F. Molecular landscape of acquired resistance to targeted therapy combinations in BRAF mutant colorectal cancer. Cancer Res 2016. PubMed
  • Ahronian LG, Corcoran RB. Effective MAPK Inhibition is critical for therapeutic responses in colorectal cancer with BRAF mutations. Mol Cell Oncol 2016; 3:e1048405. PubMed
  • Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, Mussolin B, Kwak EL, Buscarino M, Lazzari L, Valtorta E, Truini M, Jessop NA, Robinson HE, Hong TS, Mino-Kenudson M, Di Nicolantonio F, Thabet A, Sartore-Bianchi A, Siena S, Iafrate AJ, Bardelli A, Corcoran RB. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. 2015. PubMed
  • Corcoran RB, Atreya CE, Falchook GS, Kwak EL, Ryan DP, Bendell JC, Hamid O, Messersmith WA, Daud A, Kurzrock R, Pierobon M, Sun P, Cunningham E, Little S, Orford K, Motwani M, Bai Y, Patel K, Venook AP, Kopetz S. Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. J Clin Oncol 2015. PubMed
  • Kwak EL, Ahronian LG, Siravegna G, Mussolin B, Godfrey JT, Clark JW, Blaszkowsky LS, Ryan DP, Lennerz JK, Iafrate AJ, Bardelli A, Hong TS, Corcoran RB. Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer. 2015; 5:1271-81. PubMed
  • Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, Ponzetti A, Cremolini C, Amatu A, Lauricella C, Lamba S, Hobor S, Avallone A, Valtorta E, Rospo G, Medico E, Motta V, Antoniotti C, Tatangelo F, Bellosillo B, Veronese S, Budillon A, Montagut C, Racca P, Marsoni S, Falcone A, Corcoran RB, Di Nicolantonio F, Loupakis F, Siena S, Sartore-Bianchi A, Bardelli A. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 2015; 21:795-801. PubMed
  • Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, Ponzetti A, Cremolini C, Amatu A, Lauricella C, Lamba S, Hobor S, Avallone A, Valtorta E, Rospo G, Medico E, Motta V, Antoniotti C, Tatangelo F, Bellosillo B, Veronese S, Budillon A, Montagut C, Racca P, Marsoni S, Falcone A, Corcoran RB, Di Nicolantonio F, Loupakis F, Siena S, Sartore-Bianchi A, Bardelli A. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 2015; 21:827. PubMed
  • Ahronian LG, Sennott EM, Van Allen EM, Wagle N, Kwak EL, Faris JE, Godfrey JT, Nishimura K, Lynch KD, Mermel CH, Lockerman EL, Kalsy A, Gurski JM, Bahl S, Anderka K, Green LM, Lennon NJ, Huynh TG, Mino-Kenudson M, Getz G, Dias-Santagata D, Iafrate AJ, Engelman JA, Garraway LA, Corcoran RB. Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. 2015. PubMed
  • Atreya CE, Corcoran RB, Kopetz S. Expanded RAS: refining the patient population. J Clin Oncol 2015; 33:682-5. PubMed
  • Corcoran RB, Rothenberg SM, Hata AN, Faber AC, Piris A, Nazarian RM, Brown RD, Godfrey JT, Winokur D, Walsh J, Mino-Kenudson M, Maheswaran S, Settleman J, Wargo JA, Flaherty KT, Haber DA, Engelman JA. TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma. Sci Transl Med 2013; 5:196ra98. PubMed
  • 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 interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 2013; 23:121-8. PubMed
  • Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, Brown RD, Della Pelle P, Dias-Santagata D, Hung KE, Flaherty KT, Piris A, Wargo JA, Settleman J, Mino-Kenudson M, Engelman JA. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. 2012; 2:227-35. PubMed
  • Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, Lifshits E, Ryan DP, Meyerhardt JA, Benes C, Settleman J, Wong KK, Cantley LC, Engelman JA. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest 2011. PubMed
  • Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, Incio J, Digumarthy SR, Pollack SF, Song Y, Muzikansky A, Lifshits E, Roberge S, Coffman EJ, Benes CH, Gómez HL, Baselga J, Arteaga CL, Rivera MN, Dias-Santagata D, Jain RK, Engelman JA. BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. 2012; 1:352-65. PubMed
  • Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH, Levy DE, Settleman J, Engelman JA, Bardeesy N. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 2011; 71:5020-9. PubMed
  • Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal 2010; 3:ra84. PubMed
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