2. Academic Validation
  3. Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma

Low-dose triple drug combination targeting the PI3K/AKT/mTOR pathway and the MAPK pathway is an effective approach in ovarian clear cell carcinoma

  • Cancer Lett. 2019 Oct 1;461:102-111. doi: 10.1016/j.canlet.2019.07.004.
Joseph J Caumanns 1,  Anne van Wijngaarden 2,  Arjan Kol 1,  Gert J Meersma 1,  Mathilde Jalving 3,  René Bernards 4,  Ate G J van der Zee 1,  G Bea A Wisman 1,  Steven de Jong 5
Affiliations

Affiliations

  • 1 Department of Gynecologic Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
  • 2 Department of Gynecologic Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands; Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
  • 3 Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
  • 4 Division of Molecular Carcinogenesis and Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands.
  • 5 Department of Medical Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands. Electronic address: s.de.jong@umcg.nl.
PMID: 31319139 DOI: 10.1016/j.canlet.2019.07.004
Abstract

Advanced stage ovarian clear cell carcinoma (OCCC) is poorly responsive to platinum-based chemotherapy and has an unfavorable prognosis. Previous studies revealed heterogeneous mutations in PI3K/Akt/mTOR and MAPK pathway nodules converging in mTORC1/2 activation. Here, we aimed to identify an effective low-dose combination of PI3K/Akt/mTOR pathway and MAPK pathway inhibitors simultaneously targeting key kinases in OCCC to preclude single-inhibitor initiated pathway rewiring and limit toxicity. Small molecule inhibitors of mTORC1/2, PI3K and MEK1/2 were combined at monotherapy IC20 doses in a panel of genetically diverse OCCC cell lines (n = 7) to determine an optimal low-dose combination. The IC20 dose triple combination reduced kinase activity in PI3K/Akt/mTOR and MAPK pathways, prevented single-inhibitor induced feedback mechanisms and inhibited short and long-term proliferation in all seven cell lines. Finally, this low-dose triple drug combination treatment significantly reduced tumor growth in two genetically characterized OCCC patient-derived xenograft (PDX) models without resulting in weight loss in these mice. The effectiveness and tolerability of this combined therapy in PDX models warrants clinical exploration of this treatment strategy for OCCC and might be applicable to other Cancer types with a similar genetic background.

Keywords

Combination treatment; MAPK; Ovarian clear cell carcinoma; PDX models; PI3K/AKT/mTOR.

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