TY - JOUR
T1 - Combined MEK and Bcl-2/XL inhibition is effective in high-grade serous ovarian cancer patient–derived xenograft models and BIM levels are predictive of responsiveness
AU - Iavarone, Claudia
AU - Zervantonakis, Ioannis K.
AU - Selfors, Laura M.
AU - Palakurthi, Sangeetha
AU - Liu, Joyce F.
AU - Drapkin, Ronny
AU - Matulonis, Ursula A.
AU - Hallberg, Dorothy
AU - Velculescu, Victor E.
AU - Leverson, Joel D.
AU - Sampath, Deepak
AU - Mills, Gordon B.
AU - Brugge, Joan S.
N1 - Funding Information:
J.F. Liu is a consultant/advisory board member for AstraZeneca, Tesaro, Merck, Clovis, and Mersana. R. Drapkin is a consultant/advisory board member for Repare Therapeutics and Siamab Therapeutics. U.A. Matulonis is a consultant/advisory board member for Mersana, Geneos, Myriad, Clovis, Merck, 2X, Eli Lilly, Genentech, Immunogen, Fujifilm, Cerulean, and AstraZeneca. V.E. Velculescu has ownership interest (including stock, patents, etc.) in Personal Genome Diagnostics and Ignyta and is a consultant/advisory board member for Personal Genome Diagnostics and Ignyta. J.D. Leverson has ownership interest (including stock, patents, etc.) in AbbVie. G.B. Mills reports receiving a commercial research grant from Pfizer Pharmaceuticals and AstraZeneca, reports
Funding Information:
We thank the Neurobiology Imaging Facility/HNDC Enhanced Neuro-Imaging Core and the ICCB-Longwood Screening Facility at Harvard Medical School for providing access to instruments; Qing Zheng, Shan Zhou, and Vilmos Adleff for technical assistance; Geoffrey Shapiro, Dennis Slamon, and Gottfried Konecny for helpful scientific discussions; and Angelica Martinez-Gakidis for scientific editing. This work was supported by a grant from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (J.S. Brugge, R. Drapkin, G.B. Mills, D. Hallberg, and V.E. Velculescu), Breast Cancer Res Foundation (U.A. Matulonis), Ovarian Cancer Res Fund Alliance (U.A. Matulonis), and NIH grant CA121113 (V.E. Velculescu), and K99CA222554 (I.K. Zervantonakis).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/3
Y1 - 2019/3
N2 - Most patients with late-stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient–derived xenograft models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the proapoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death, and displayed synergy in vitro in most models. In vivo, GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models—those with high BIM at baseline that was increased with MEK inhibition and those with low basal BIM and high pERK levels. Models with low BIM and low pERK were nonresponsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for the clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.
AB - Most patients with late-stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient–derived xenograft models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the proapoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death, and displayed synergy in vitro in most models. In vivo, GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models—those with high BIM at baseline that was increased with MEK inhibition and those with low basal BIM and high pERK levels. Models with low BIM and low pERK were nonresponsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for the clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.
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U2 - 10.1158/1535-7163.MCT-18-0413
DO - 10.1158/1535-7163.MCT-18-0413
M3 - Article
C2 - 30679390
AN - SCOPUS:85065247196
SN - 1535-7163
VL - 18
SP - 642
EP - 655
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 3
ER -