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CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress

Feng Li1, David Kozono1, Peter Deraska2

  • 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Molecular Cell
|October 27, 2020
PubMed

Insights

The gene FAM122A helps cancer cells become resistant to CHK1 inhibitors by increasing WEE1 protein levels. Targeting FAM122A or using combination therapy can overcome this resistance, improving anti-cancer drug efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Emerging drug resistance to CHK1 inhibitors (CHK1is) poses a significant challenge in cancer therapy.
  • Understanding resistance mechanisms is crucial for developing effective anti-cancer strategies.

Purpose of the Study:

  • To investigate the role of the FAM122A gene in cellular resistance to CHK1 inhibitors.
  • To elucidate the molecular mechanisms underlying FAM122A-mediated resistance.
  • To identify potential therapeutic strategies to overcome CHK1 inhibitor resistance.

Main Methods:

  • CRISPR-mediated gene knockout of FAM122A.
  • Analysis of protein dephosphorylation and degradation pathways.
  • Assessment of WEE1 protein expression and its impact on replication stress and cell cycle checkpoints.
  • Evaluation of combination therapy using CHK1 and WEE1 inhibitors in resistant tumor cells.

Main Results:

  • FAM122A knockout confers resistance to CHK1 inhibitors and cross-resistance to ATR inhibitors.
  • FAM122A knockout activates the PP2A-B55α phosphatase, leading to WEE1 dephosphorylation and increased WEE1 protein stability.
  • Elevated WEE1 levels reduce replication stress and activate the G2/M checkpoint, conferring resistance.
  • CHK1 phosphorylates FAM122A in response to oncogene-driven replication stress, activating PP2A-B55α and increasing WEE1.
  • Combination therapy with CHK1 and WEE1 inhibitors overcomes resistance in FAM122A-expressing tumor cells.

Conclusions:

  • FAM122A plays a critical role in mediating resistance to CHK1 inhibitors through the WEE1 pathway.
  • FAM122A expression levels can serve as a predictive biomarker for CHK1 inhibitor sensitivity.
  • Targeting FAM122A or combining CHK1 and WEE1 inhibitors offers a promising strategy to enhance anti-cancer therapy.
Keywords:
CHK1 inhibitorCRISPR sgRNA screeningFAM122AFanconi AnemiaPABIR1PP2AWEE1

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