Abstract IA008: Targeting homologous recombination deficiency (HRD) using optimized ionizing radiation and drug combinations

Abstract

Abstract Homologous recombination deficiency (HRD) is found not only in germline mutation carriers of HR genes but is also observed in sporadic cancers when both copies of the HR gene are inactivated. Recognition of HRD is facilitated by using genomic landscape alterations in addition to target gene sequencing. In addition, HR function can be established by measuring RAD51 foci in tumor specimens, particularly if they are irradiated ex-vivo to reveal the HR pathway function more clearly. Triple negative breast cancer (TNBC) is highly enriched for HRD constituting ~45% of primary tumors and over 50% of locally recurrent or metastatic cancers. In a clinical trial of recurrent TNBC, we used the combination of ionizing radiation (IR) with low-dose weekly cisplatin (cis) to study the clinical response according to HRD status. The combination of IR + cis has been shown in HRD cells to be more sensitizing than either agent alone. In the clinical study of 49 TNBC patients, there were imaging responses in 22/29 (75%) HRD patients, but only in 4/20 (20%) HR-proficient patients. We have followed this study by investigating the combination of the PARP-inhibitor with radiotherapy in an ongoing clinical trial as well as with detailed cell-based studies. HRD cells have elevated PARP activity at baseline, as observed by the extent of PARylated proteins, plus the lower baseline levels of NAD. When PARP-inhibitors are combined with radiotherapy, there is demonstrable supra-additive sensitization at 6Gy of IR and up to 100nM talazoparib (TZ). However, when the dose of TZ is above 1 µM, there is paradoxical recovery from the combination therapy, due to rescue of NAD depletion in HRD cells. The threshold for seeing this paradoxical recovery effect in HR-proficient cells was not reached. One of the mechanisms of cell killing in HRD cells is enhanced parthanatos, which higher doses of TZ will prevent, particularly in conjunction with IR. The implication of this work is that the optimal combination of radiotherapy with PARP-inhibitor may not be the maximum tolerated dose, but rather a tuned level of the combination to maximize radiosensitization without exceeding the threshold for PARP-inhibitor mediated protection of cell death. It is already observed that the maximum tolerated dose of PARP-inhibitor in the setting of curative doses of IR have to be modified by 3-10-fold. Further optimization of the combination dosing to achieve the maximal therapeutic ratio will be discussed including the development of biomarkers to achieve this goal. Additional radiation combinations with synthetic lethal targets of HRD will be discussed. Citation Format: Simon N. Powell, Niamh McDermott, Robert Delsite. Targeting homologous recombination deficiency (HRD) using optimized ionizing radiation and drug combinations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA008.