PARP1-SNAI2 transcription axis drives resistance to PARP inhibitor, Talazoparib

Abstract

The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.

PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer

“…In addition, PARP1 protein has been shown to regulate SNAI2 transcription by influencing the chromatin accessibility around SNAI2 promoters. Talazoparib treatment has been demonstrated to drive SNAI2 transcription and confer drug resistance [ 54 ]. Here, our findings indicate that PARPi treatment facilitates DOT1L transcription and drug resistance.…”

Establishment and Molecular Characterization of an In Vitro Model for PARPi-Resistant Ovarian Cancer

“…These findings can likely be interpreted as basal cellular adaption mechanisms in response to drug exposure. Particularly EMT has already been described as an adaptive response to therapy, independent of clonal selection [41], and has been associated with intrinsic and acquired resistance to talazoparib [15].…”

“…There is an ongoing pre-clinical effort to discover novel regulators of PARPi response based on various in vitro models of PARPi resistance [15][16][17][18]. These approaches provide insight into resistance pathways, which could be translated into innovative therapeutic targets.…”

“…These approaches provide insight into resistance pathways, which could be translated into innovative therapeutic targets. However, for the design of those models, numerous experimental variables need to be considered, such as (i) the genetic background of used cell lines (ii) the protocol for PARPi exposure, and (iii) the analytic resolution of the established model (cell population level vs. single cell) [15][16][17][18]. Several in vitro ovarian cancer models of PARPi resistance have been described [17,[19][20][21] with considerably varying experimental frameworks.…”