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Identifying and targeting markers of de-novo and acquired MEK-inhibitor resistance in low-grade serous ovarian carcinoma

University of British Columbia

Representing approximately 5% of all epithelial ovarian cancers, low-grade serous ovarian carcinoma (LGSC) is a rare histotype with unique genetic, molecular, and pathological features. LGSC patients are often detected at an advanced stage and respond poorly to platinum-based chemotherapy. Therefore, targeted therapies focused on exploiting oncogenic dependencies have homed in on the RAS/RAF/MEK/ERK (MAPK) signaling pathway, due to frequent activating MAPK mutations in LGSC tumours. Trials using MEK inhibitors (MEKi) have seen a modest increase in patient response, however, no cellular markers that distinguish MEKi response have been identified. This research aimed to discover and target protein markers of MEKi response by analyzing the global proteome of in-vitro cell lines previously established from patient samples through mass spectrometric analyses. 95 proteins were identified as being significantly differentially expressed between four MEKi sensitive and three MEKi resistant LGSC cell lines. Nine of these proteins were selected for further analysis, with the differentially protein expression of five markers being successfully validated. One of these confirmed markers, EGFR (a common driver of oncogenesis), was selected for paired inhibition with MEK using a combination of small molecule inhibitors specific for MEK and EGFR to induce cellular apoptosis in MEKi resistant LGSC lines. Four de novo and three acquired MEKi resistant LGSC cell lines were treated with a combination of erlotinib (EGFRi) and either selumetinib or trametinib (MEKi’s). Cellular response was analyzed by live-cell imaging, cell proliferation, and viability assays. A linear mixed effects model and drug synergism analysis was implemented to evaluate the efficacy of MEKi and EGFRi in combination. In the four de novo resistant LGSC lines, the drug combination induced complete cell death in two lines and demonstrated a degree of drug synergism in another. In the acquired MEKi resistance setting however, none of the cell lines responded to dual EGFR and MEK inhibition. Therefore, the combined inhibition of EGFR and MEK may represent a potential therapy for overcoming de novo MEKi resistance in LGSC, but not as a strategy for combatting acquired MEKi resistance.

Text

2022-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/72762

Reproductive and Developmental Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/