Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance

Abstract

Background and Rationale: Synthetic lethality (SL)-based strategies hold significant promise for overcoming therapeutic resistance, a critical bottleneck in cancer treatment where cancer cells evade anticancer therapies, leading to diminished efficacy or treatment failure. The core of SL lies in exploiting tumour-specific vulnerabilities: drug-resistant cells often acquire unique genetic defects or compensatory adaptive responses, and SL strategies selectively target genes or pathways dependent on these vulnerabilities to induce specific cell death, thereby reversing resistance.

Content and Focus: This review systematically elaborates on SL mechanisms and the multi-faceted nature of tumour drug resistance, then focuses on how SL counteracts resistant phenotypes by leveraging resistant cells’ vulnerabilities. We further delineate SL applications in preclinical resistance models, highlight representative SL-related drugs and predictive biomarkers and critically analyse challenges in clinical translation.

Conclusion: By integrating mechanistic insights, preclinical validation and translational perspectives, this review aims to provide novel insights for precision therapy and a foundational reference to advance SL strategies in overcoming tumour resistance and facilitating their clinical implementation.

Keywords

cancer therapeutic resistance / clinical translation / DNA damage response reprogramming / genome-scale CRISPR screening / synthetic lethality

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