Clonal evolution and resistance mechanisms inBRAF-driven EGFR-mutated lung cancer

Despite the clinical success of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), acquired resistance remains a key limitation for the treatment of non-small cell lung cancer (NSCLC). This study investigates co-occurring EGFR and BRAF mutations at initial diagnosis and as resistance mechanism after EGFR-TKI therapy in a cohort of patients. Using whole-exome sequencing (WES) of multiple biopsies from individual patients provided insights into the clonal evolution of detected subclones and their respective mechanisms of resistance as well as their origin. The findings of multiple studies have shown that cells with co-occurring EGFR and KRAS mutations exhibit synthetic lethality1–3 . This work explored whether simultaneous overexpression of EGFR and BRAF could result in a similar synthetic lethal cytotoxic effect. Our functional studies revealed that patient-derived NSCLC cells harbouring co-expression of EGFRdel19 and BRAFV600E mutations are resistant to EGFR-TKI therapy through sustained activation of the MAPK signalling pathway. However, no fitness disadvantages or synthetic lethality were observed. The study demonstrated that BRAFV600E in EGFR-mutant NSCLC is a robust and relevant mechanism of resistance against EGFR TKI therapy. The study also highlighted the clinical relevance of BRAF mutations in NSCLC patients and the potential to overcome MAPK pathway-mediated resistance through combined vertical inhibition of EGFR and MEK1/2. This combination therapy of osimertinib and trametinib suppressed tumour growth in vitro and in in vivo mouse xenograft models.