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Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition. | LitMetric

AI Article Synopsis

  • * Found that BCAR1 interacts with mutant KRAS and is crucial for the phosphorylation of p130Cas, which is linked to MYC transcription regulation.
  • * Demonstrated that using a combination of SRC/tubulin inhibitors with ERK inhibitors effectively reduces MYC protein and hinders the growth of KRAS mutant pancreatic cancer cells.

Article Abstract

To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-β-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the βIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340308PMC
http://dx.doi.org/10.1016/j.celrep.2021.109291DOI Listing

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