Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance

Violeta Serra, Anderson T. Wang, Marta Castroviejo-Bermejo, Urszula M. Polanska, Marta Palafox, Andrea Herencia-Ropero, Gemma N. Jones, Zhongwu Lai, Joshua Armenia, Filippos Michopoulos, Alba Llop-Guevara, Rachel Brough, Aditi Gulati, Stephen J. Pettitt, Krishna C. Bulusu, Jenni Nikkil€a, Zena Wilson, Adina Hughes, Paul W.G. Wijnhoven, Ambar AhmedAlejandra Bruna, Albert Gris-Oliver, Marta Guzman, Olga Rodríguez, Judit Grueso, Joaquin Arribas, Javier Cortés, Cristina Saura, Alan Lau, Susan Critchlow, Brian Dougherty, Carlos Caldas, Gordon B. Mills, J. Carl Barrett, Josep V. Forment, Elaine Cadogan, Christopher J. Lord, Cristina Cruz, Judith Balmaña, Mark J. O'Connor

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Purpose: PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance. Experimental Design: We analyzed breast and ovarian patientderived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models. Results: Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress. Conclusions: Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi.

Original languageEnglish (US)
Pages (from-to)4536-4550
Number of pages15
JournalClinical Cancer Research
Issue number20
StatePublished - Oct 15 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance'. Together they form a unique fingerprint.

Cite this