Université Paris-Saclay, Institut Gustave Roussy, Inserm, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, 94800, Villejuif, France.
Department of Medical Biology and Pathology, Gustave Roussy Cancer Centre, Villejuif, France.
Eur J Cancer. 2020 Jun;132:211-223. doi: 10.1016/j.ejca.2020.03.025. Epub 2020 May 6.
BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAF V600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAF NSCLC.
Patients with BRAF NSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array.
Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1 K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and rat sarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb).
Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.
BRAF 是一种已被证实的非小细胞肺癌（NSCLC）治疗靶点，因为 BRAF 抑制剂达拉非尼联合 MEK 抑制剂曲美替尼已被批准用于治疗携带 BRAF V600E 突变的 NSCLC。然而，关于 BRAF NSCLC 对 BRAF/MEK 抑制剂产生耐药的机制，目前仅有少量证据。
本机构前瞻性 MATCH-R（“耐药配对”）试验纳入了对 BRAF/MEK 抑制剂获得性耐药的 BRAF NSCLC 患者，并在影像学进展时进行肿瘤和液体活检。进行了广泛的分子分析，包括靶向下一代测序（NGS）、全外显子组测序（WES）、RNA 测序和比较基因组杂交（CGH）阵列。
在纳入的 11 名患者中，8 名患者在接受达拉非尼-曲美替尼联合治疗后进展，2 名患者在接受达拉非尼单药治疗后进展，1 名患者在接受维莫非尼（BRAF 抑制剂）治疗后进展。其中 7 名患者的分子分析完整，而另外 1 名患者仅有靶向 NGS 和 CGH 阵列数据。在这 8 名患者中，有 3 名在接受达拉非尼-曲美替尼联合治疗后进展的患者中检测到潜在的耐药相关分子事件，即 MEK1 K57N、RAS 病毒（v-ras）致癌基因同源物（NRAS）Q61R 和大鼠肉瘤病毒致癌基因同源物（KRAS）Q61R 突变。1 名在接受达拉非尼单药治疗后进展的患者发生了 PTEN 移码突变。在其余 4 名接受分析的患者中，没有发现耐药的分子线索。对 7 名患者进行的 WES 评估显示肿瘤突变负担较低（中位数=2.06 个突变/兆碱基，范围=1.57-3.75 mut/Mb）。
在 BRAF NSCLC 中发现了对 BRAF/MEK 抑制剂的新耐药机制，这突出了 MAPK 通路的反复参与，并为新的治疗策略的发展提供了指导。
