P66ShcA potentiates the cytotoxic response of triple-negative breast cancers to PARP inhibitors.

Eduardo Cepeda Cañedo,Deanna Macneil,Jesse Hudson,Morag Park,Paul Savage,Ryuhjin Ahn,Stephanie Totten,Chantal Autexier,Josie Ursini-Siegel,Michael Witcher,Genevieve Deblois

doi:10.1172/jci.insight.138382

Abstract

Triple-negative breast cancers (TNBCs) lack effective targeted therapies, and cytotoxic chemotherapies remain the standard of care for this subtype. Owing to their increased genomic instability, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are being tested against TNBCs. In particular, clinical trials are now interrogating the efficacy of PARPi combined with chemotherapies. Intriguingly, while response rates are low, cohort of patients do respond to PARPi in combination with chemotherapies. Moreover, recent studies suggest that an increase in levels of ROS may sensitize cells to PARPi. This represents a therapeutic opportunity, as several chemotherapies, including doxorubicin, function in part by producing ROS. We previously demonstrated that the p66ShcA adaptor protein is variably expressed in TNBCs. We now show that, in response to therapy-induced stress, p66ShcA stimulated ROS production, which, in turn, potentiated the synergy of PARPi in combination with doxorubicin in TNBCs. This p66ShcA-induced sensitivity relied on the accumulation of oxidative damage in TNBCs, rather than genomic instability, to potentiate cell death. These findings suggest that increasing the expression of p66ShcA protein levels in TNBCs represents a rational approach to bolster the synergy between PARPi and doxorubicin.

Highlights

Triple-negative breast cancers (TNBCs) are a clinically relevant subtype of breast cancer encompassing tumors that lack expression of the estrogen receptor (ER), progesterone receptor, and human epithelial growth factor receptor 2 (HER2) [1, 2]
To test whether p66ShcA levels are predictive of increased chemoresponsiveness in TNBCs, we employed several TNBC patient–derived xenografts (PDXs) that were derived from primary breast cancers before any therapeutic intervention
Clinical trials showed a lack of objective clinical responses in women with sporadic TNBC compared with those with BRCA1/2 mutated breasts cancers, who most benefited from this targeted therapy [59, 60]

Summary

Introduction

Triple-negative breast cancers (TNBCs) are a clinically relevant subtype of breast cancer encompassing tumors that lack expression of the estrogen receptor (ER), progesterone receptor, and human epithelial growth factor receptor 2 (HER2) [1, 2]. TNBC accounts for approximately 15%–20% of all newly diagnosed breast cancer cases and is associated with poor prognosis [1,2,3,4]. Unlike ER-positive and HER2-positive breast tumors, the poor outcomes of individuals diagnosed with TNBC is mediated, in part, by the lack of effective targeted therapies. Relapse is commonly observed within the first 5 years after diagnosis. This early relapse is often characterized by the formation of visceral metastases. At relapse, these tumors are generally resistant to the chemotherapies used as standard of care, and the average life expectancy is reduced to less than 18 months [1]

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