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

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

doi:10.1016/j.celrep.2021.109291

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.

Authors

Andrew M Waters¹, Tala O Khatib¹, Bjoern Papke¹, Craig M Goodwin¹, G Aaron Hobbs², J Nathaniel Diehl³, Runying Yang², A Cole Edwards⁴, Katherine H Walsh⁵, Rita Sulahian⁵, James M McFarland⁵, Kevin S Kapner⁶, Thomas S K Gilbert⁷, Clint A Stalnecker¹, Sehrish Javaid⁸, Anna Barkovskaya⁹, Kajal R Grover¹⁰, Priya S Hibshman⁴, Devon R Blake¹¹, Antje Schaefer², Katherine M Nowak¹¹, Jennifer E Klomp¹, Tikvah K Hayes³, Michelle Kassner¹², Nanyun Tang¹², Olga Tanaseichuk¹³, Kaisheng Chen¹³, Yingyao Zhou¹³, Manpreet Kalkat¹⁴, Laura E Herring¹⁵, Lee M Graves², Linda Z Penn¹⁴, Hongwei H Yin¹², Andrew J Aguirre¹⁶, William C Hahn¹⁶, Adrienne D Cox¹⁷, Channing J Der¹⁸

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: cjder@med.unc.edu.

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

Acetamides
Crk-Associated Substrate Protein
KRAS protein, human
Morpholines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Pyridines
Tubulin
tirbanibulin
src-Family Kinases
Extracellular Signal-Regulated MAP Kinases
Calpain
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding