BRAF G466A

Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

Furthermore, TP53, LRP1B, STK11, SPTA1and MAGI2 were significantly over-mutated in Class II and III (p<0.06) and SETD2 is over-mutated in Class I (p<0.001), might suggesting relatively poor prognosis in NSCLC patients. Conclusions The characteristics of Chinese NSCLC were further explored, including BRAF mutation types, the incidence of related co-mutations and TMB value, which is helpful to formulate targeted therapy strategies to adapt to different types of BRAF mutation functions according to their genomic and clinical characteristics.

The study highlights the heterogeneity of patients with BRAF class II and class III regarding histology and co-mutational status, with both classes equally frequent. A more granular investigation of non-V600X alterations and their associated clinical outcomes under different treatment approaches is ongoing.

All the uncommon mutants displayed higher sensitivity than both the wild type and BRAF-V600E towards PLX 8394 and LSN3074753...Notably, molecular dynamic (MD) simulation revealed that increased number of interactions caused enhanced sensitivity of G469R and N581S towards sorafenib. RAF kinase inhibitors were further classified into two groups as per their selectivity (Group I: BRAF-V600E-selective and Group II: CRAF-selective) based on which potential mutation-wise combinations of RAF kinase inhibitors were proposed to overcome resistance. Based on computational inhibitor sensitivity profiles, appropriate treatment strategies may be devised to prevent or overcome secondary drug resistance in lung cancer patients with uncommon mutations.

Funding: Novartis Pharmaceuticals Corporation. Clinical trial identification: NCT02974725.