Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer

Abstract

BackgroundTriple-negative breast cancer (TNBC) shows aggressive clinical behavior, but the treatment options are limited due to lack of a specific target. TNBC shares many clinical and pathological similarities with BRCA-deficient breast cancer, for which poly(ADP-ribose) polymerase (PARP) inhibitor is effective, but PARP inhibitor alone failed to show clinical effects in patients with sporadic TNBC. Radiation induces DNA double-strand breaks, and the phosphoinositide 3-kinase (PI3K) signaling pathway has been known to regulate steady-state levels of homologous recombination. A recent preclinical study showed that PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient TNBC to PARP inhibition. Therefore, we assessed the radiosensitizing effect, and the underlying mechanism of combination treatment with PARP inhibitor olaparib and PI3K inhibitor PI-103 in BRCA-proficient TNBC cells.MethodsMDA-MB-435S cells were divided into four treatment groups, irradiation (IR) alone, olaparib plus IR, PI-103 plus IR, and olaparib plus PI-103 plus IR. Cells were exposed to the drugs for 2 hours prior to irradiation, and the cell survival curve was obtained using a clonogenic assay. Western blotting and immunofluorescent detection of γH2AX foci were performed. Xenograft and bioluminescence imaging were carried out to assess in vivo radiosensitivity.ResultsCombined use of olaparib and PI-103 enhanced radiation-induced death of MDA-MB-435S (sensitizer enhancement ratio[SER]0.05,1.7) and MDA-MB-231-BR (SER0.05,2.1) cells and significantly reduced tumor volume in a xenograft models (P < 0.001). Treatment with PI-103 showed persistent γH2AX foci, indicating delayed repair of DNA strand breaks. PI-103 alone increased levels of poly(ADP-ribose) and phosphorylated extracellular signal-regulated kinase, and downregulated BRCA1.ConclusionsCombined use of olaparib and PI-103 enhanced radiation-induced cell death in BRCA-proficient MDA-MB-435S and MDA-MB-231-BR cells and xenografts. TNBC patients have high incidences of locoregional relapse and distant metastasis, and radiation therapy targets both locoregional control and treatment of distant recurrences such as brain metastasis or other oligometastasis. Targeting of the PI3K signaling pathway combined with PARP inhibition maybe a feasible approach to enhance effects of radiation in BRCA-proficient TNBC.

Dual PI3K- and mTOR-inhibitor PI-103 can either enhance or reduce the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in tumor cells: The role of drug-irradiation schedule

“…In addition, PI-103 can radiosensitize prostate [34], colorectal [35] and breast [36, 37] cancer cells alone or in a combination with a PARP inhibitor olaparib [37]. …”

Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation

“…Many preclinical and clinical studies have been performed to determine RT response in different molecular subtypes of breast cancer, and sensitivity to radiation seems to be higher in hormone-positive tumors as compared to that of HER2-type or TNBC [6]. To enhance the effects of RT in TNBC, several agents have been investigated in preclinical studies [5,7]. Cell cycle checkpoints are often deregulated in cancer cells, and thus, have been used as therapeutic targets.…”

PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond

“…Similarly, radiation was used by Jang et al, to induce the burden of DNA DSBs. They reported that radiosensitization with combined use of olaparib and PI-103 has found to be efficacious in a xenograft model of TNBC [70]. Efficacy of carboplatin alone and in combination with ABT888 in Intracranial murine models of BRCA-mutated and BRCA-wild-type TNBC is also reported by Karginova et al [76].…”