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

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.Electronic supplementary materialThe online version of this article (10.1186/s12935-019-0725-1) contains supplementary material, which is available to authorized users.

Low‐grade serous ovarian carcinoma: A comprehensive literature review

“…As discussed, responsiveness to MEKi is limited to a subset of patients. A recent study sought to identify predictive biomarkers for response to MEKi in LGSOC cell lines . Researchers found MEKi sensitive cell lines had KRAS mutations and low levels of epithelial growth factor receptor (EGFR) and PKC‐alpha protein expression .…”

“…A recent study sought to identify predictive biomarkers for response to MEKi in LGSOC cell lines . Researchers found MEKi sensitive cell lines had KRAS mutations and low levels of epithelial growth factor receptor (EGFR) and PKC‐alpha protein expression . These biomarkers may lead to better patient selection for MEKi and points to the potential benefits of combination therapies such as EGFR inhibitors (EGFRi) and MEKi .…”

“…Researchers found MEKi sensitive cell lines had KRAS mutations and low levels of epithelial growth factor receptor (EGFR) and PKC‐alpha protein expression . These biomarkers may lead to better patient selection for MEKi and points to the potential benefits of combination therapies such as EGFR inhibitors (EGFRi) and MEKi . Other combination therapies which may hold promise include MEKi and BRAFi which have shown improved survival in BRAF ‐mutant melanoma patients and BRAFi with EGFRi which have shown improved tumour regression in BRAF ‐mutant colorectal cancer xenografts …”

“…MEKi. 42 an omentectomy and traditionally pelvic and para-aortic lymphadenectomy followed by histological review by a dedicated gynaecological pathologist. 47 However, as noted, the role of lymphadenectomy in early stage disease is not fully established and may not confer a PFS or OS benefit.…”

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

“…In the last few years, we have established a large collection of cancer cell line models from advanced/recurrent LGSOC patients [22]. These models have since then been used for pre-clinical drug testing and biomarker discovery in several studies [22][23][24]. With the introduction of MEKi therapy for…”