SYNTHETIC lethality could counter cancer drug resistance by targeting tumor vulnerabilities that appear after treatment pressures.
Why Cancer Treatments Stop Working
Therapeutic resistance remains one of the most persistent barriers in oncology, often turning early response into relapse or treatment failure. A new review explores how synthetic lethality approaches may help address this challenge by identifying weaknesses that resistant tumor cells become reliant on as they adapt to therapy.
At its core, synthetic lethality describes a paired dependency: a tumor may tolerate disruption of one pathway, but becomes unable to survive when a second, linked pathway is targeted. Drug-resistant cancer cells frequently accumulate genetic defects or develop compensatory adaptive responses, creating tumor-specific vulnerabilities. Synthetic lethality strategies aim to exploit those vulnerabilities to induce selective cell death, while sparing non-malignant cells that do not share the same dependencies.
How Synthetic Lethality Turns Resistance Into a Target
The review outlines the multi-layered biology behind tumour drug resistance, including shifting pathway reliance and reprogramming of survival mechanisms such as the DNA damage response. Rather than viewing resistance as an endpoint, the authors frame it as an opportunity to reveal new therapeutic targets that only emerge once cancer cells have been pressured by prior therapies.
The authors also describe how synthetic lethality is being explored across a range of preclinical resistance models, including approaches that use genome-scale CRISPR screening to map genetic dependencies. These models can help pinpoint which pathways resistant tumour cells cannot live without, enabling a more rational route to combination therapy design and resistance-informed treatment strategies.
From Lab Insight to Clinical Translation
Moving from mechanism to patient impact depends on two major factors: identifying the right synthetic lethal targets, and finding predictive biomarkers that can reliably match patients to benefit. The review highlights representative synthetic lethality-related drugs and biomarker strategies under investigation, while also addressing the practical challenges of clinical translation, including tumor heterogeneity, evolving resistance, and the complexity of validating biomarkers in real-world settings.
By integrating mechanistic insight, preclinical evidence, and translational priorities, the authors position synthetic lethality as a precision therapy framework with potential to extend response durability in resistant cancers.
Reference: Li J et al. Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance. Clin Transl Med. 2026;16(1):e70586.
