RAF1 extrachromosomal DNA amplification confers acquired erlotinib resistance in a non-small cell lung cancer cell model

Abstract

EGFR (epidermal growth factor receptor)-targeted therapies, which utilize small molecule inhibitors such as erlotinib and osimertinib to inhibit aberrantly activated EGF receptors caused by oncogenic mutations such as L858R and exon 19 deletion occurring primarily in the region coding its kinase domain, have demonstrated significant clinical efficacy in various cancers, particularly non-small cell lung cancer (NSCLC). 1 Nevertheless, a substantial challenge to the long-term effectiveness of these therapies is the inevitable development of drug resistance. Resistance typically arises through secondary EGFR mutations (e.g., T790M, C797S), activation of bypass pathways such as MET or ERBB2 amplification, or phenotypic transformations including small-cell conversion or EMT. 1