ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition

Abstract

SUMMARY Intrinsic resistance and RTK-RAS-MAPK pathway reactivation has limited the effectiveness of MEK and RAF inhibitors (MAPKi) in RAS- and RAF-mutant cancers. To identify genes that modulate sensitivity to MAPKi, we performed genome scale CRISPR-Cas9 loss-of-function screens in two KRAS-mutant pancreatic cancer cell lines treated with the MEK1/2 inhibitor trametinib. Loss of CIC, a transcriptional repressor of ETV1, 4, and 5, promoted survival in the setting of MAPKi in cancer cells derived from several lineages. ATXN1L deletion, which reduces CIC protein, or ectopic expression of ETV1, 4, or 5 also modulated sensitivity to trametinib. ATXN1L expression inversely correlates with response to MAPKi inhibition in clinical studies. These observations identify the ATXN1L-CIC-ETS transcription factor axis as a mediator of resistance to MAPKi.

Transcriptomic definition of molecular subgroups of small round cell sarcomas

“…While the CIC-NUTM1 fusion was discovered as a new brain tumour entity [14], we show here that they are encompassed in a homogeneous CIC-fused group of tumours together with CIC-DUX4-and CIC-FOXO4-positive samples [27]. The overexpression of genes of the PEA3 type of the ETS family observed in all CIC-fused samples is known to be a consequence of a loss of function of CIC [28], which was also involved in resistance to MAPK inhibitors [28,29] or in the promotion of metastasis [30]. Further analyses should confirm whether a dominant negative effect on wild-type CIC is a consequence of CIC fusions and if it may be correlated with the aggressiveness of CIC-fused tumours.…”

A double‐edged sword: The world according to Capicua in cancer

“…As CIC suppresses MAPK downstream signals, downregulation of CIC may be one of the resistance mechanisms for targeted therapies. Indeed, reduced expression of ATXN1L that abrogates the CIC function are found to promote resistance to MAPK pathway inhibition in KRAS mutated pancreatic cancer cells . In this study, Wang et al .…”

“…Indeed, reduced expression of ATXN1L that abrogates the CIC function are found to promote resistance to MAPK pathway inhibition in KRAS mutated pancreatic cancer cells. (65) In this study, Wang et al identified CIC as a gene that modulates the sensitivity for MEK1/2 inhibitor trametinib by CRISPR/Cas9-mediated screening. The exact mechanism to explain how ATXN1L is downmodulated to reduce CIC protein and sensitivity to trametinib remains to be investigated, however, the result suggests importance of the ATXN1L-CIC axis for targeted therapy against the genetic mutations in the RTK/RAS/MAPK pathway (Fig.…”

COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors

“…The prevalence of alterations in the COP1/DET1/CSN pathway in mediating clinical resistance is not known, given the limited number of available samples at this time and the large number of players in this pathway. In addition, 2 recent publications showed that loss of the tumor suppressor CIC, a well-known transcriptional suppressor of Pea3-ETS factors, conveyed resistance to MEK inhibition in pancreatic cancer (44) and EGFR inhibition in non-small-cell lung cancer (NSCLC) (45). These studies highlight the multiple mechanisms that modulate Pea3-ETS factor levels in shaping the response to MAPK inhibition.…”