Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the EGFR gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include MET amplification, EGFR C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, PD-L1 and KRAS amplifications and ESR1-AKAP12 and MKRN1-BRAF translocations, as well as BRAF V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of EGFR-mutant NSCLC developing a BRAF V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context.

中文翻译：

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靶向 BRAF 激活作为 EGFR 突变非小细胞肺癌中 EGFR 酪氨酸激酶抑制剂的获得性耐药机制

奥希替尼已成为晚期非小细胞肺癌 (NSCLC) 的一线治疗标准，其中EGFR基因中存在外显子 19 和 21 激活突变。尽管如此，18.9 个月的中位无进展生存期强调了对奥希替尼治疗的耐药性是不可避免的事实。EGFR 驱动的 NSCLC 中奥希替尼的获得性耐药机制包括MET扩增、EGFR C797S 突变、神经内分泌分化、小细胞肺癌组织学转化、PD-L1和KRAS扩增以及ESR1-AKAP12和MKRN1-BRAF易位，以及BRAFV600 突变。最后一个代表了 3% 的奥希替尼获得性耐药机制。在这篇综述中，我们根据EGFR突变 NSCLC的临床病例讨论 EGFR/BRAF/MEK 联合抑制的基本原理，该病例发生BRAF V600 突变作为对奥希替尼的获得性耐药机制，并对奥希替尼加达拉非尼的关联做出反应和曲美替尼。此外，我们讨论了在这种情况下对奥希替尼加达拉非尼和曲美替尼组合的获得性耐药机制。