Markers of MEK inhibitor resistance in low-grade serous ovarian cancer: EGFR is a potential therapeutic target

Marta Llaurado Fernandez,Mattia Cremona,Bryan Hennessy,Trevor Shepherd,Colin C Collins,Clara Salamanca,Mark S Carey,Joshua Hoenisch,Amy Dawson,Sylvia Bamford,Hannah Kim,David G Huntsman,Stanislav Volik,Shawn Anderson,Gabriel Dimattia

doi:10.1186/s12935-019-0725-1

Abstract

BackgroundAlthough low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. LGSC respond to MEKi only in a subgroup of patients, so predictive biomarkers and better therapies will be needed.MethodsWe evaluated a number of patient-derived LGSC cell lines, previously classified according to their MEKi sensitivity. Two cell lines were genomically compared against their matching tumors samples. MEKi-sensitive and MEKi-resistant lines were compared using whole exome sequencing and reverse phase protein array. Two treatment combinations targeting MEKi resistance markers were also evaluated using cell proliferation, cell viability, cell signaling, and drug synergism assays.ResultsLow-grade serous ovarian cancer cell lines recapitulated the genomic aberrations from their matching tumor samples. We identified three potential predictive biomarkers that distinguish MEKi sensitive and resistant lines: KRAS mutation status, and EGFR and PKC-alpha protein expression. The biomarkers were validated in three newly developed LGSC cell lines. Sub-lethal combination of MEK and EGFR inhibition showed drug synergy and caused complete cell death in two of four MEKi-resistant cell lines tested.ConclusionsKRAS mutations and the protein expression of EGFR and PKC-alpha should be evaluated as predictive biomarkers in patients with LGSC treated with MEKi. Combination therapy using a MEKi with EGFR inhibition may represent a promising new therapy for patients with MEKi-resistant LGSC.

Highlights

Low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective
Recognizing the challenges using IC-50 values to assess drug efficacy invitro, we established a stringent definition of MEK inhibitors (MEKi) sensitivity/resistance recognizing that only 15% of patients with advanced/recurrent low-grade serous ovarian cancer (LGSC) will show tumor experience regression when treated with a MEKi
Either mutation was present in 28.6% of all cell lines/cultures, and in 36.4% (KRAS) and 27.3% (NRAS) respectively when analyzed by patient

Summary

Introduction

Low-grade serous ovarian cancer (LGSC) is rare, case-fatality rates are high as most patients present with advanced disease and current cytotoxic therapies are not overly effective. Recognizing that these cancers may be driven by MAPK pathway activation, MEK inhibitors (MEKi) are being tested in clinical trials. Evidence of MAPK pathway activation in LGSC [21] led to a key clinical trial evaluating the efficacy of the MEK inhibitor (MEKi) selumetinib for the treatment of patients with advanced and/or recurrent LGSC (GOG-0239) The results from this trial, published in 2013, shown a 15% response rate and 65% disease stabilization [22]. An international randomized phase II/III clinical trial using the MEKi trametinib is ongoing (NCT02101788) and a translational research component to better understand the molecular mechanisms of MEKi efficacy is included

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