American Association for Cancer Research
Browse
can-22-0391_figure_s1_page2_suppsf1-2.png (1.94 MB)

Figure S1 page2 from Combination Therapies with CDK4/6 Inhibitors to Treat KRAS-Mutant Pancreatic Cancer

Download (1.94 MB)
figure
posted on 2023-03-31, 05:43 authored by Craig M. Goodwin, Andrew M. Waters, Jennifer E. Klomp, Sehrish Javaid, Kirsten L. Bryant, Clint A. Stalnecker, Kristina Drizyte-Miller, Bjoern Papke, Runying Yang, Amber M. Amparo, Irem Ozkan-Dagliyan, Elisa Baldelli, Valerie Calvert, Mariaelena Pierobon, Jessica A. Sorrentino, Andrew P. Beelen, Natalie Bublitz, Mareen Lüthen, Kris C. Wood, Emanuel F. Petricoin, Christine Sers, Autumn J. McRee, Adrienne D. Cox, Channing J. Der

Figure S1 page2

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

American Cancer Society (ACS)

Royster Society of Fellows

Pancreatic Cancer Action Network (PCAN)

Sky Foundation (THE SKY FOUNDATION)

Deutsche Forschungsgemeinschaft (DFG)

Slomo and Cindy Silvian Foundation

National Institutes of Health (NIH)

U.S. Department of Defense (DOD)

Lustgarten Foundation (LustgartenFDN)

Julie M. Brown and Christina Gianoplus Colon Cancer Foundation

History

ARTICLE ABSTRACT

Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK–MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K–AKT–mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor–based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC. CRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer.

Usage metrics

    Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC