THERAPEUTIC POTENTIAL OF TARGETING LACTATE DEHYDROGENASE C IN TRIPLE NEGATIVE BREAST CANCER

Abstract

Triple negative breast cancer (TNBC) patients face poor prognosis due to early relapse and chemoresistance, emphasizing the need for novel therapeutic strategies. Lactate Dehydrogenase C (LDHC), a cancer/testis antigen with tumor-specific expression, has emerged as a promising anti-cancer target. Previously, we showed that targeting LDHC improves response to DNA damage response-related drugs like olaparib. In this study, we investigated the role of LDHC in olaparib resistance and identified associated molecular mechanisms. In addition, we developed a novel cell penetrating peptide-based approach to target LDHC in TNBC. In the first part of this study, TNBC cell lines with stable LDHC silencing were used to study transcriptomic changes under olaparib treatment. Short-term treatment led to transcriptomic changes related to transmembrane transport, endoplasmic reticulum stress, and cell death. Development of olaparib resistance was associated with alterations in cell migration, proliferation and pluripotency genes such as PRKD1, ERBB4, Wnt6 and Wnt7b, which have been implicated in chemoresistance. LDHC-silenced cells with early resistance showed loss of expression of the tumor-suppressor genes OVOL1 and SOX15, while fully resistant cells displayed increased expression of LPAR1, a gene associated with cellular senescence. These findings highlight distinct molecular mechanisms underlying olaparib resistance after LDHC targeting, providing potential therapeutic targets to overcome resistance and enhance therapeutic efficacy. In the second part of this study, we validated a cell-penetrating peptide (CPP)-based siRNA approach with RGD-mediated tumor homing properties to target LDHC. Four different CPP:siRNA nanocomplexes (10R, 10R-RGD, cRGD-10R and iRGD-10R) were characterized for stability, cellular uptake, LDHC knockdown efficiency and cytotoxicity. The 10R-RGD:siLDHC and cRGD-10R:siLDHC complexes showed the highest LDHC knockdown efficiency, reduced TNBC clonogenicity and enhanced olaparib response. Lastly, these two nanocomplexes significantly reduced tumor burden in a TNBC xenograft zebrafish model without any major toxicity. Taking together, our results suggest that CPP-based siRNA delivery provides a novel and safe approach to target LDHC, either as monotherapy or in combination with chemotherapy.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences