Faculty Collaboration Database

Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition. Cell Rep 2021 Jun 29;35(13):109291

Date

07/01/2021

Pubmed ID

34192548

Pubmed Central ID

PMC8340308

DOI

10.1016/j.celrep.2021.109291

Scopus ID

2-s2.0-85108871908 (requires institutional sign-in at Scopus site)   19 Citations

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.

Author List

Waters AM, Khatib TO, Papke B, Goodwin CM, Hobbs GA, Diehl JN, Yang R, Edwards AC, Walsh KH, Sulahian R, McFarland JM, Kapner KS, Gilbert TSK, Stalnecker CA, Javaid S, Barkovskaya A, Grover KR, Hibshman PS, Blake DR, Schaefer A, Nowak KM, Klomp JE, Hayes TK, Kassner M, Tang N, Tanaseichuk O, Chen K, Zhou Y, Kalkat M, Herring LE, Graves LM, Penn LZ, Yin HH, Aguirre AJ, Hahn WC, Cox AD, Der CJ

Author

Antje Schaefer PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetamides
Apoptosis
Calpain
Cell Line, Tumor
Cell Proliferation
Crk-Associated Substrate Protein
Down-Regulation
Drug Synergism
Extracellular Signal-Regulated MAP Kinases
Gene Expression Regulation, Neoplastic
Half-Life
Humans
Microtubules
Morpholines
Mutation
Organoids
Pancreatic Neoplasms
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Proto-Oncogene Proteins p21(ras)
Pyridines
Transcription, Genetic
Tubulin
Xenograft Model Antitumor Assays
src-Family Kinases