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SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Philip Bland1, Harry Saville1, Patty T Wai1

  • 1The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

Nature Genetics
|July 31, 2023
PubMed

Insights

SF3B1 mutations predict poor outcomes, but SF3B1 mutant cells are sensitive to PARP inhibitors (PARPi). This sensitivity stems from defective DNA repair, offering a new therapeutic strategy for SF3B1-mutant cancers.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Genetics

Background:

  • SF3B1 hotspot mutations are linked to poor prognosis across various cancers.
  • These mutations cause widespread disruption of canonical RNA splicing.
  • Understanding the vulnerabilities of SF3B1-mutant cells is crucial for targeted therapies.

Purpose of the Study:

  • To identify therapeutic vulnerabilities in SF3B1-mutant cancer cells.
  • To investigate the mechanism underlying sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi).
  • To evaluate the in vivo efficacy of PARPi in SF3B1-mutant cancer models.

Main Methods:

  • Synthetic lethal drug screens were employed to identify drugs targeting SF3B1 mutant (SF3B1MUT) cells.
  • Cellular responses to PARPi-induced replication stress were analyzed.
  • The role of cyclin-dependent kinase 2 interacting protein (CINP) and DNA damage response pathways (CHK1, ATM) was investigated.
  • In vivo studies utilized SF3B1MUT cancer models to assess PARPi efficacy.

Main Results:

  • SF3B1MUT cells exhibit selective sensitivity to PARPi, irrespective of mutation site or tumor origin.
  • These cells show a compromised response to PARPi-induced replication stress due to CINP downregulation.
  • This leads to increased replication origin firing, reduced pCHK1 (S317) induction, and failure to arrest the cell cycle.
  • CINP overexpression rescues these defects, and combination therapy with ATM and PARP inhibitors shows promise.
  • PARPi demonstrated significant antitumor effects and reduced metastasis in vivo.

Conclusions:

  • SF3B1 mutations create a vulnerability to PARPi by impairing DNA replication stress response.
  • Targeting this vulnerability with PARPi offers a potential therapeutic strategy for SF3B1MUT cancers.
  • Clinical trials of PARPi in biomarker-selected, homologous recombination proficient patients are warranted.

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