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Waters AM, Khatib TO, Papke B, et al. Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition. Cell Rep. 2021;35(13):109291doi: 10.1016/j.celrep.2021.109291.
Waters, A. M., Khatib, T. O., Papke, B., Goodwin, C. M., Hobbs, G. A., Diehl, J. N., Yang, R., Edwards, A. C., Walsh, K. H., Sulahian, R., McFarland, J. M., Kapner, K. S., Gilbert, T. S. K., Stalnecker, C. A., Javaid, S., Barkovskaya, A., Grover, K. R., Hibshman, P. S., Blake, D. R., Schaefer, A., Nowak, K. M., Klomp, J. E., Hayes, T. K., Kassner, M., Tang, N., Tanaseichuk, O., Chen, K., Zhou, Y., Kalkat, M., Herring, L. E., Graves, L. M., Penn, L. Z., Yin, H. H., Aguirre, A. J., Hahn, W. C., Cox, A. D., & Der, C. J. (2021). Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition. Cell reports, 35(13), 109291. https://doi.org/10.1016/j.celrep.2021.109291
Waters, Andrew M, et al. "Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition." Cell reports vol. 35,13 (2021): 109291. doi: https://doi.org/10.1016/j.celrep.2021.109291
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. Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition. Cell Rep. 2021 Jun 29;35(13):109291. doi: 10.1016/j.celrep.2021.109291. PMID: 34192548; PMCID: PMC8340308.
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Cell Rep. 2021 Jun 29;35(13):109291. doi: 10.1016/j.celrep.2021.109291.

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

Cell reports

Andrew M Waters, Tala O Khatib, Bjoern Papke, Craig M Goodwin, G Aaron Hobbs, J Nathaniel Diehl, Runying Yang, A Cole Edwards, Katherine H Walsh, Rita Sulahian, James M McFarland, Kevin S Kapner, Thomas S K Gilbert, Clint A Stalnecker, Sehrish Javaid, Anna Barkovskaya, Kajal R Grover, Priya S Hibshman, Devon R Blake, Antje Schaefer, Katherine M Nowak, Jennifer E Klomp, Tikvah K Hayes, Michelle Kassner, Nanyun Tang, Olga Tanaseichuk, Kaisheng Chen, Yingyao Zhou, Manpreet Kalkat, Laura E Herring, Lee M Graves, Linda Z Penn, Hongwei H Yin, Andrew J Aguirre, William C Hahn, Adrienne D Cox, Channing J Der

Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  3. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  5. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  6. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  7. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  8. Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  9. Institute for Cancer Research, Oslo University Hospital, Oslo 0379, Norway.
  10. Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  11. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  12. Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, AZ 85004, USA.
  13. Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
  14. Department of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada.
  15. UNC Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  16. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Brigham and Women's Hospital, Boston, MA 02215, USA.
  17. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  18. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Oral and Craniofacial Biomedicine PhD Program, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].

PMID: 34192548 PMCID: PMC8340308 DOI: 10.1016/j.celrep.2021.109291

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.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: BCAR1; ERK; KRAS; MYC; TUBB3; calpain; microtubules; p130Cas; pancreatic cancer; β-catenin

Conflict of interest statement

Declaration of interests C.J.D. has received funding from and is a consultant for and advisory board member of Mirati Therapeutics and Deciphera Pharmaceuticals. C.J.D. has consulted for Eli Lilly, Ja

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