Combining STING Agonists with PARP Inhibitors Mounts an NK-Dependent Defense against Therapy-Resistant Breast Cancer.

Abstract

Breast cancers with BRCA1 or BRCA2 mutations are defective in repair of DNA double-strand breaks by homologous recombination, resulting in compensatory error-prone repair that causes genomic instability. Poly(ADP-ribose) polymerase inhibitors (PARPi) are FDA-approved to treat homologous recombination-defective cancers, inducing therapy responses by synthetic lethality. PARPis increase micronuclei formation and cytosolic double-stranded DNA accumulation, activating stimulator of interferon genes (STING). Activation of STING can mediate anticancer innate immune responses by increasing T-cell infiltration into the tumor microenvironment. However, PARPi responses are not durable, and therapy resistance ensues with limited therapeutic options available for these patients. Using PARPi-sensitive and -resistant patient-derived xenografts and mouse-derived allografts, Pedretti and colleagues show in this issue of Cancer Research that the PARPi olaparib in combination with the next-generation STING agonist diABZI can overcome PARPi resistance in a manner dependent on NK cell function in the tumor microenvironment. Their study highlights a novel component of the STING-dependent innate immune response repertoire required for fighting PARPi-resistant cancer. Potent and specific next-generation STING agonists are being tested in the clinic in solid and liquid tumors, indicating a resurgence of these drugs after a long period of modest clinical activity, with a special focus on combination therapy strategies to fight therapy-resistant cancer. See related article by Pedretti et al., p. 1888.