Journal
MOLECULAR CELL
Volume 80, Issue 3, Pages 410-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2020.10.008
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Funding
- National Institutes of Health [R37HL052725, P01HL048546]
- Department of Defense [BM110181, BC151331P1]
- Breast Cancer Research Foundation
- Fanconi Anemia Research Fund
- Public Health Service [R35CA232128, P01CA203655, K08CA172354, F31CA189328]
- Joint Center for Radiation Therapy
- Eli Lilly
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While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A/PABIR1 confers cellular resistance to CHK1 inhibitors (CHK1is) and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55 alpha, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1is. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55a phosphatase and increased WEE1 expression. A combination of a CHK1i plus a WEE1 inhibitor can overcome CHK1i resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1i sensitivity or resistance.
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