Multiomics characterization of low-grade serous ovarian carcinoma identifies potential biomarkers of MEK inhibitor sensitivity and therapeutic vulnerability.

Abstract:

:Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here we use multiomics integration of whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics on fourteen LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data to LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines. Distinct patterns of COSMIC mutational signatures were identified in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes were more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. These LGSOC cell lines were representative models of the molecular aberrations found in LGSOC tumors. For prediction of in vitro MEKi efficacy, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines. This study suggests that CDKN2A/B or MTAP deficiency may be exploited using synthetically lethal treatment strategies, highlighting the importance of using proteomic data as a tool for molecular drug prediction. Multiomics approaches are crucial to improving our understanding of the molecular underpinnings of LGSOC and applying this information to develop new therapies.

journal_name

Cancer Res

journal_title

Cancer research

authors

Shrestha R,Llaurado Fernandez M,Dawson A,Hoenisch J,Volik S,Lin YY,Anderson S,Kim H,Haegert AM,Colborne S,Wong NKY,McConeghy B,Bell RH,Brahmbhatt S,Lee CH,DiMattia GE,Le Bihan S,Morin GB,Collins CC,Carey MS

doi

10.1158/0008-5472.CAN-20-2222

subject

Has Abstract

pub_date

2021-01-13 00:00:00

eissn

0008-5472

issn

1538-7445

pii

0008-5472.CAN-20-2222

pub_type

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