2. Academic Validation
  3. CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress

CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress

  • Mol Cell. 2020 Nov 5;80(3):410-422.e6. doi: 10.1016/j.molcel.2020.10.008.
Feng Li 1,  David Kozono 1,  Peter Deraska 2,  Timothy Branigan 3,  Connor Dunn 2,  Xiao-Feng Zheng 1,  Kalindi Parmar 2,  Huy Nguyen 2,  James DeCaprio 3,  Geoffrey I Shapiro 4,  Dipanjan Chowdhury 1,  Alan D D'Andrea 5
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 2 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 01115.
  • 4 Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 01115; Early Drug Development Center, Dana-Farber Cancer Institute, Boston, MA 02215.
  • 5 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: alan_dandrea@dfci.harvard.edu.
PMID: 33108758 DOI: 10.1016/j.molcel.2020.10.008
Abstract

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-B55α, 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-B55α 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.

Keywords

CHK1 inhibitor; CRISPR sgRNA screening; FAM122A; Fanconi Anemia; PABIR1; PP2A; WEE1.

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