American Association for Cancer Research
Browse
mcr-23-0034_supplementary_figure_legends_1-7_suppsm1-7.docx (15.09 kB)

Supplementary Figure Legends 1-7 from CBF-Beta Mitigates PI3K-Alpha–Specific Inhibitor Killing through PIM1 in PIK3CA-Mutant Gastric Cancer

Download (15.09 kB)
journal contribution
posted on 2023-11-01, 08:01 authored by Lyla J. Stanland, Hazel X. Ang, Jacob P. Hoj, Yunqiang Chu, Patrick Tan, Kris C. Wood, Micah A. Luftig

S1. BYL719 and DMSO beta scores S2. Ribbon plots of non-gastric cancer cell lines included in screen. S3. Dasatinib renders AGS cells hyper-sensitive to BYL719 S4. Loss of BCL-XL induces cell death in BYL719 treated MKN1 S5. BCL-XL inhibitor A-1331852 is the only inhibitor capable of increasing BYL719-induced cell death and inhibiting cell growth. S6. CBFB binding co-factor RUNX1 is down-regulated at protein and mRNA level in BYL719 resistant clones. S7. Pan-PIM inhibition or PIM1 KO re-sensitizes CBFB KO and resistant clones to BYL719.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

Find out more...

Duke Cancer Institute (DCI)

Duke-NUS Medical School (DukeNUS)

Nicholas School of the Environment, Duke University

History

ARTICLE ABSTRACT

PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4%–25% of gastric cancers display activating PIK3CA mutations, including 80% of Epstein–Barr virus–associated GCs. Small molecules, including pan-PI3K and dual PI3K/mTOR inhibitors, have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform-specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study, we identified modulators of the response to the PI3Kα-specific inhibitor, BYL719, in PIK3CA-mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hypersensitivity to BYL719, through increased cell-cycle arrest and cell death, respectively. In addition, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to upregulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3Kα inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3Kα inhibitor response in PIK3CA-mutant gastric tumors and can inform future work as mutant-selective inhibitors are in development for diverse tumor types. Loss of either NEDD9 or BCL-XL confers hypersensitivity to PI3K-alpha inhibition whereas loss of CBFB confers resistance through a CBFB/PIM1 signaling axis.