Di Federico Alessandro, Angelicola Stefania, Frascino Mariateresa, Siracusa Irene, Bisanti Beatrice, Ruzzi Francesca, Semprini Maria Sofia, De Jonge Hugo, De Giglio Andrea, Sperandi Francesca, Brocchi Stefano, Melotti Barbara, Giunchi Francesca, Gruppioni Elisa, Altimari Annalisa, Lollini Pier-Luigi, Ardizzoni Andrea, Palladini Arianna, Gelsomino Francesco
Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
JCO Precis Oncol. 2024 Dec;8:e2400240. doi: 10.1200/PO.24.00240. Epub 2024 Dec 5.
Patients with tumors harboring class 3 mutations lack targeted therapies. These mutations are characterized by low/absent BRAF kinase domain activation and are believed to amplify already active RAS signaling, potentially triggered by receptor tyrosine kinases like EGFR.
Two patients with class 3-mutated metastatic non-small-cell lung cancer (NSCLC) were treated with erlotinib at our Institution after failure of standard therapies. Two cell lines were established from patients with class 3-mutated NSCLC, and their sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs) was assessed using mutated, class 1 and 2-mutated, and -mutated NSCLC cell lines as controls.
Patient 1, a 60-year-old male with BRAF-mutated NSCLC, achieved complete response to erlotinib after progression on first- and second-line chemotherapy. Patient 2, a 60-year-old female with BRAF-mutated NSCLC, achieved partial response to erlotinib after progression on first-line chemoimmunotherapy. High baseline phosphorylated EGFR values and reduced EGFR activation following erlotinib were observed in class 3-mutated and -mutated cell lines, but not in class 1-mutated, class 2-mutated, or -mutated lines. Erlotinib inhibited 2-dimensional growth in class 3-mutated cell lines (IC 6.33 and 7.11 µM) and in the class 2-mutated cell line (IC 5.51 µM), albeit at higher concentrations than in -mutated lines, whereas it showed no effect on class 1-mutated (IC, >25 µM) or -mutated (IC, >25 µM) lines. These findings were corroborated by 3-dimensional and sphere formation assays. In the Cancer Cell Line Encyclopedia, class 3-mutated NSCLC cell lines showed greater sensitivity to EGFR-TKIs compared with class 2-mutated and -mutated lines.
class 3 mutations in NSCLC may identify a novel targetable population sensitive to EGFR-TKIs.
携带3类突变的肿瘤患者缺乏靶向治疗方法。这些突变的特征是BRAF激酶结构域激活程度低/无激活，并且被认为会放大已激活的RAS信号传导，这可能由受体酪氨酸激酶如EGFR触发。
在我们机构，两名患有3类突变转移性非小细胞肺癌（NSCLC）的患者在标准治疗失败后接受了厄洛替尼治疗。从患有3类突变NSCLC的患者中建立了两个细胞系，并以突变的、1类和2类突变的以及野生型NSCLC细胞系作为对照，评估了它们对EGFR酪氨酸激酶抑制剂（EGFR-TKIs）的敏感性。
患者1是一名60岁患有BRAF突变NSCLC的男性，在一线和二线化疗进展后对厄洛替尼实现了完全缓解。患者2是一名60岁患有BRAF突变NSCLC的女性，在一线化疗免疫治疗进展后对厄洛替尼实现了部分缓解。在3类突变和野生型细胞系中观察到高基线磷酸化EGFR值以及厄洛替尼治疗后EGFR激活降低，但在1类突变、2类突变或野生型细胞系中未观察到。厄洛替尼抑制了3类突变细胞系（IC50为6.33和7.11µM）和2类突变细胞系（IC50为5.51µM）的二维生长，尽管其浓度高于野生型细胞系，而对1类突变（IC50，>25µM）或野生型（IC50，>25µM）细胞系无影响。这些发现通过三维和球体形成试验得到了证实。在癌症细胞系百科全书中，3类突变NSCLC细胞系与2类突变和野生型细胞系相比，对EGFR-TKIs表现出更高的敏感性。
NSCLC中的3类突变可能确定了一个对EGFR-TKIs敏感的新的可靶向人群。
