Combined MEK and Bcl-2/X L inhibition is effective in high-grade serous ovarian cancer patient–derived xenograft models and BIM levels are predictive of responsiveness

Claudia Iavarone, Ioannis K. Zervantonakis, Laura M. Selfors, Sangeetha Palakurthi, Joyce F. Liu, Ronny Drapkin, Ursula A. Matulonis, Dorothy Hallberg, Victor E. Velculescu, Joel D. Leverson, Deepak Sampath, Gordon Mills, Joan S. Brugge

Research output: Contribution to journalArticle

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Abstract

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/X L 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/X L 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.

Original languageEnglish (US)
Pages (from-to)642-655
Number of pages14
JournalMolecular cancer therapeutics
Volume18
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Heterografts
Ovarian Neoplasms
MAP Kinase Signaling System
Drug Combinations
Proteomics
Proto-Oncogene Proteins c-bcl-2
Cell Death
Therapeutics
Cell Count
GDC-0973
Apoptosis
Recurrence
Drug Therapy
Growth
Neoplasms
navitoclax

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Combined MEK and Bcl-2/X L inhibition is effective in high-grade serous ovarian cancer patient–derived xenograft models and BIM levels are predictive of responsiveness . / Iavarone, Claudia; Zervantonakis, Ioannis K.; Selfors, Laura M.; Palakurthi, Sangeetha; Liu, Joyce F.; Drapkin, Ronny; Matulonis, Ursula A.; Hallberg, Dorothy; Velculescu, Victor E.; Leverson, Joel D.; Sampath, Deepak; Mills, Gordon; Brugge, Joan S.

In: Molecular cancer therapeutics, Vol. 18, No. 3, 01.03.2019, p. 642-655.

Research output: Contribution to journalArticle

Iavarone, C, Zervantonakis, IK, Selfors, LM, Palakurthi, S, Liu, JF, Drapkin, R, Matulonis, UA, Hallberg, D, Velculescu, VE, Leverson, JD, Sampath, D, Mills, G & Brugge, JS 2019, ' Combined MEK and Bcl-2/X L inhibition is effective in high-grade serous ovarian cancer patient–derived xenograft models and BIM levels are predictive of responsiveness ', Molecular cancer therapeutics, vol. 18, no. 3, pp. 642-655. https://doi.org/10.1158/1535-7163.MCT-18-0413
Iavarone, Claudia ; Zervantonakis, Ioannis K. ; Selfors, Laura M. ; Palakurthi, Sangeetha ; Liu, Joyce F. ; Drapkin, Ronny ; Matulonis, Ursula A. ; Hallberg, Dorothy ; Velculescu, Victor E. ; Leverson, Joel D. ; Sampath, Deepak ; Mills, Gordon ; Brugge, Joan S. / Combined MEK and Bcl-2/X L inhibition is effective in high-grade serous ovarian cancer patient–derived xenograft models and BIM levels are predictive of responsiveness In: Molecular cancer therapeutics. 2019 ; Vol. 18, No. 3. pp. 642-655.
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abstract = "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/X L 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/X L 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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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

AU - Brugge, Joan S.

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