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

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posted on 2023-04-01, 00:06 authored by 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 Nikkilä, Zena Wilson, Adina Hughes, Paul W.G. Wijnhoven, Ambar Ahmed, Alejandra 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
Supplementary Figure from Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance

Funding

Instituto de Salud Carlos III (ISCIII)

European Research Area-NET

Fundación Científica Asociación Española Contra el Cáncer (AECC)

Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)

Fundació la Marató de TV3 (Fundació la Marató)

Fundación Fero (Fundació Fero)

Departament de Salut, Generalitat de Catalunya (Department of Health, Government of Catalonia)

Agencia Estatal de Investigación (AEI)

Breast Cancer Research Foundation (BCRF)

Cancer Research UK (CRUK)

EIT Health

National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

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. We analyzed breast and ovarian patient-derived 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. 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. 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.

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    Clinical Cancer Research

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    cancer

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    CC BY

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