Overcoming Drug Resistance in Lung Cancer: New Strategies Emerge

Despite significant advancements in cancer treatment, particularly with EGFR tyrosine kinase inhibitors (TKIs) for EGFR-mutant non-small-cell lung cancer (NSCLC), drug resistance remains a persistent obstacle. From early first-generation inhibitors like erlotinib and gefitinib to the current standard-of-care third-generation covalent inhibitor osimertinib, primary or acquired resistance to these agents inevitably emerges via diverse mechanisms.

The therapeutic landscape is rapidly evolving, with a growing focus on combination therapies. These novel approaches integrate chemotherapy, anti-angiogenic agents, bispecific antibodies, or antibody-drug conjugates, showing promise in enhancing clinical benefit. However, this progress also introduces new resistance phenotypes, underscoring the dynamic plasticity and complexity of tumor evolution under therapeutic pressure.

A critical shift is occurring in how resistance is monitored and managed. The paradigm is moving from traditional radiological assessments to sophisticated molecular monitoring. Advances in circulating tumor DNA (ctDNA) analysis, artificial intelligence (AI), and multi-omics technologies are paving the way for more adaptive treatment strategies.

Ultimately, a more complete mechanistic understanding of resistance is paramount. As lead author Zhao notes in the paper, "As the therapeutic landscape evolves, a more complete mechanistic understanding of resistance will be essential to guide rational treatment sequencing, inform trial design and improve long-term outcomes for patients with EGFR-mutant NSCLC." This comprehensive understanding also underpins the development of proactive strategies to pre-empt resistance.