Synergism of PARP inhibitor fluzoparib (HS10160) and MET inhibitor HS10241 in breast and ovarian cancer cells

by Selleckchem | Sep 21 2023

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are promising targeted therapeutics for breast and ovarian cancers bearing a germline BRCA1/2 mutation (BRCA m), and several have already received regulatory approval in the United States. In patients with a BRCA m cancer, PARPi can increase the burden of unrepaired DNA double-strand breaks by blocking PARP activity and trapping PARP1 onto damaged DNA. Resistance to PARP inhibitors can block the formation of DNA double-strand breaks through BRCA-related DNA repair pathway. MET is a hyper-activated receptor tyrosine kinase expressed in multiple cancer types and the activation contributes to resistance to DNA damage-inducing therapeutic drugs. Our previous study showed that MET inhibition by pan-kinase inhibitors has synergism with PARPi in suppressing growth of breast cancer in vitro and in xenograft tumor models. In this study, we validated the inhibitory effect of novel inhibitors, HS10241 (selective MET inhibitor) and HS10160 (PARPi), to their target respectively in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC) cells. We further demonstrated that these two inhibitors function synergistically in eliminating TNBC and HGSOC cells; combining with HS10241 increased DNA double-strand breaks induced by HS10160 in cancer cells; and PARP1 tyrosine (Y)-907 phosphorylation (PARP1 p-Y907) can be an effective biomarker as an indicator of MET-mediated PARPi in HGSOC. Our results suggest that the combination of HS10241 and HS10160 may benefit patients bearing tumors overexpressing MET as well as those resistant to single-agent PARPi treatment.

Comments:

The paragraph you provided describes a study that investigated the potential of combining a selective MET inhibitor (HS10241) with a PARP inhibitor (HS10160) for the treatment of triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). The study aimed to validate the inhibitory effects of these two inhibitors on their respective targets and explore their synergistic potential in eliminating cancer cells.

The rationale behind this combination therapy is based on previous research that identified MET, a hyper-activated receptor tyrosine kinase, as a contributor to resistance against DNA damage-inducing therapeutic drugs. The study mentioned that MET activation can impede the formation of DNA double-strand breaks, which are crucial for the effectiveness of PARP inhibitors in cancer treatment. By inhibiting MET using HS10241 and simultaneously blocking PARP activity with HS10160, the researchers aimed to enhance the elimination of TNBC and HGSOC cells.

The study conducted experiments using TNBC and HGSOC cells to validate the inhibitory effects of HS10241 and HS10160 on their respective targets. The researchers also demonstrated that the combination of these two inhibitors had a synergistic effect in eliminating cancer cells. Importantly, the combination of HS10241 and HS10160 increased the levels of DNA double-strand breaks induced by HS10160 alone, which suggests that MET inhibition can enhance the efficacy of PARP inhibitors in promoting DNA damage.

Additionally, the study identified PARP1 tyrosine (Y)-907 phosphorylation (PARP1 p-Y907) as a potential biomarker for MET-mediated PARP inhibitor response in HGSOC. This finding suggests that the phosphorylation of PARP1 at tyrosine 907 could serve as an indicator of the efficacy of the combination therapy in HGSOC patients.

Overall, the results of this study indicate that the combination of HS10241 (MET inhibitor) and HS10160 (PARP inhibitor) may be beneficial for patients with TNBC and HGSOC. This combination therapy has the potential to overcome resistance to single-agent PARP inhibitor treatment, particularly in tumors overexpressing MET. However, further research and clinical trials are needed to validate these findings and determine the safety and efficacy of this combination therapy in a clinical setting.