Combating tumor PARP inhibitor resistance: Combination treatments, nanotechnology, and other potential strategies

Abstract

PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi) have demonstrated significant potential in cancer treatment, particularly in tumors with breast cancer susceptibility gene (BRCA) mutations and other DNA repair deficiencies. However, the development of resistance to PARPi has become a major challenge in their clinical application. The emergence of drug resistance leads to reduced efficacy of the PARPi over time, impacting long-term treatment outcomes and survival rates. PARPi resistance in tumors often arises as cells activate alternative DNA repair pathways or evade the effect of PARPi, diminishing therapeutic effectiveness. Consequently, overcoming resistance is crucial for maintaining treatment efficacy and improving patient prognosis. This paper reviews the strategies to overcome PARPi resistance through combination treatment and nanotechnology therapy. We first review the current combination therapies with PARPi, including anti-angiogenic therapies, radiotherapies, immunotherapies, and chemotherapies, and elucidate their mechanisms for overcoming PARPi resistance. Additionally, this paper focuses on the application of nanotechnology in improving the effectiveness of PARPi and overcoming drug resistance. Subsequently, this paper presents several promising strategies to tackle PARPi resistance, including but not limited to: structural modifications of PARPi, deployment of gene editing systems, implementation of “membrane lipid therapy,” and modulation of cellular metabolism in tumors. By integrating these strategies, this research will provide comprehensive approaches to overcome the resistance of PARPi in cancer treatment and offer guidance for future research and clinical practice.