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Cancer Cell Int. 2019 Jan 8;19:10. doi: 10.1186/s12935-019-0725-1. eCollection 2019.

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

Author information

1
1Obstetrics and Gynecology, University of British Columbia, Vancouver, BC Canada.
2
2Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada.
3
3Translational Ovarian Cancer Research Program, London Health Science Centre, London, ON Canada.
4
4Oncology, University of Western Ontario, London, ON Canada.
5
Medical Oncology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
6
6Laboratory for Advanced Genome Analysis, Vancouver Prostate Centre, Vancouver, BC Canada.
7
7Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC Canada.
8
Division of Gynecologic Oncology, Diamond Health Centre, 2775 Laurel St., 6th Floor, Vancouver, BC V5Z 1M9 Canada.

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.

KEYWORDS:

EGFR inhibitor; MEK inhibitor; Ovarian cancer; PKC-alpha; Predictive biomarkers

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