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

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 resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms that protect cells from oncogeneinduced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity.

Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma

“…35 Recently, prexasertib-mediated acquired resistance is reported to be associated with components of innate immunity in a panel of pancancer cell line models and in vivo carcinoma and sarcoma models. 39 In our study, we also provide evidence that prexasertib-mediated acquired resistance is, at least in part, due to immune evasion. In the expression data, we observed increased expression of several immunosuppressive regulatory genes including Foxp3, Icos, Gitr, Ccr2, and xasertib resulted in treatment-related adverse events including neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue.…”

“…To date, several mechanisms of prexasertib resistance have been published including but not limited to mutations in the target gene, activation of compensatory signaling pathways, and immune evasion 38 . Recently, prexasertib‐mediated acquired resistance is reported to be associated with components of innate immunity in a panel of pan‐cancer cell line models and in vivo carcinoma and sarcoma models 39 . In our study, we also provide evidence that prexasertib‐mediated acquired resistance is, at least in part, due to immune evasion.…”

MMB-FOXM1-driven premature mitosis is required for CHK1 inhibitor sensitivity

“…Here, we demonstrated the impact of differences in CDK1 activity regulated by an MMB-FOXM1-dependent feedback loop in triggering replication catastrophe after CHK1 inhibition. LIN54 and FOXM1 were separately shown to modulate CHK1i sensitivity in ovarian and pancreatic cancer, respectively ( Blosser et al, 2020 ; Chung et al, 2019 ). This result suggests that the insights about the S/G2/M transition derived from this study could inform the use of CHK1is in additional cancer types.…”

“…Monotherapy with the CHK1 inhibitor (CHK1i) prexasertib has shown safety and tolerability ( Hong et al, 2016 , 2018 ). Prexasertib and CHK1 depletion have little to no effect on non-transformed cells such as RPE-1, whereas CHK1i mono-therapy exhibits activity in multiple cancer cell lines ( Blosser et al, 2020 ; Cole et al, 2011 ; King et al, 2015 ; Koppenhafer et al, 2018 ). However, intrinsic or acquired resistance to CHK1i may limit clinical efficacy.…”

Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation

“…Recently, it has been reported that the acquired resistance of prexasertib is associated with innate immunity [167,168]. Blosser et al [168] identified the correlation between prexasertib resistance with innate immunity genes and described the association between the sensitivity of prexasertib and the expression of E2F target genes. The expression of immune-related and E2F/ G2M/SAC genes contributes to prexasertib resistance.…”