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

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

Cancer Cell International201919:10

https://doi.org/10.1186/s12935-019-0725-1

Received: 19 October 2018
Accepted: 2 January 2019
Published: 8 January 2019

Abstract

Background

Although 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.

Methods

We 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.

Results

Low-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.

Conclusions

KRAS 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.