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Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR

Violeta Serra1,2, Anderson T Wang3, Marta Castroviejo-Bermejo1

  • 1Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|August 3, 2022
PubMed
Abstract

Insights

PARP inhibitors (PARPi) resistance can be overcome by targeting replication stress with WEE1 inhibitors (WEE1i) or ATR inhibitors (ATRi). These distinct strategies offer new therapeutic options for HRR-deficient and HRR-proficient tumors.

Area of Science:

  • Oncology
  • Cancer Therapeutics
  • DNA Repair Mechanisms

Background:

  • PARP inhibitors (PARPi) are effective against homologous recombination repair (HRR)-deficient tumors.
  • Resistance to PARPi often involves restoring HRR or protecting stalled replication forks.
  • ATR inhibition was previously considered a key strategy to overcome PARPi resistance.

Purpose of the Study:

  • To investigate WEE1 inhibitor (WEE1i) and ATR inhibitor (ATRi) as monotherapies and in combination with PARPi in PARPi-resistant models.
  • To identify biomarkers predictive of response to WEE1i and ATRi.
  • To elucidate the mechanisms by which WEE1i and ATRi overcome PARPi resistance.

Main Methods:

  • Analysis of breast and ovarian patient-derived xenoimplant models resistant to PARPi.
  • Quantification of WEE1i and ATRi responses, alone and combined with PARPi.
  • Biomarker analysis (genetic, protein), metabolite analysis, and nucleoside rescue experiments.

Main Results:

  • WEE1i response correlated with replication stress markers (STK11/RB1, phospho-RPA).
  • ATRi response was associated with ATM mutations.
  • WEE1i and ATRi combinations with olaparib presented distinct therapeutic strategies targeting replication stress.
  • WEE1i sensitivity was linked to dNTP pool depletion and increased replication stress.

Conclusions:

  • Targeting the replication stress response is a viable strategy to overcome PARPi resistance, even in tumors lacking HRR deficiency.
  • WEE1i and ATRi offer distinct approaches to reverse PARPi resistance.
  • These findings are being evaluated in ongoing clinical trials combining PARPi with WEE1i or ATRi.

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