A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib.

A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib. Oncotarget. 2020 Jan 21;11(3):216-236 Authors: Blosser WD, Dempsey JA, McNulty AM, Rao X, Ebert PJ, Lowery CD, Iversen PW, Webster YW, Donoho GP, Gong X, Merzoug FF, Buchanan S, Boehnke K, Yu C, You XT, Beckmann RP, Wu W, McNeely SC, Lin AB, Martinez R Abstract The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib ...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research