BRAF G466V

Finally, our study demonstrated that the patient benefited from the treatment of chemotherapy alone, or combined with target therapy after the operation. Meanwhile, the BRAF p.G466V, TP53 mutations, MTOR p.T1977I and exons 2-5 deletion of FLCN may be potential molecular mechanisms and oncogenic drivers of this disease.

BRAF inhibitors including vemurafenib, dabrafenib and encorafenib have produced impressive responses in V600X patients, however resistance usually emerges within a year, including RAS mutation, BRAFV600E amplification, and BRAFV600E intragenic deletion or splice variants...The combination of encorafenib and trametinib showed no activity in the same model...Based on its activity in preclinical models, including models of BRAF inhibitor resistance, and its drug-like properties we are progressing CFT1946 as a candidate for clinical development in patients with solid tumors bearing BRAF V600X mutations. Further, given CFT1946’s activity on non-V600 BRAF mutations, we are continuing to explore CFT1946 and related BiDAC degraders as therapeutic options for patients bearing Class II or Class III BRAF mutations.

17 TP53 p.R249S 18 TP53 p.R158H 19 TP53 p.S215R 20 TP53 p.P278L 21 TP53 p.R283H 22 TP53 p.P278S; TP53 p.G279E; TP53 c.375+3_375+4insG; p.? 23 TP53 p.R267Q 24 TP53 p.C238F; TP53 p.C275S 25 TP53 p.Y163C 26 TP53 p.R248W 27 TP53 p.S241F 28 TP53 p.V272G Conclusion For patients in whom molecular analysis on tissue cannot be performed, NGS analysis of cfDNA in plasma provides an opportunity to detect driver mutations for subsequent targeted therapy.

Vemurafenib and dabrafenib have already been approved for the treatment of melanoma, NSCLC and colorectal carcinoma. BRAF gene mutations, especially BRAF non-V600, was extensively mutated in Chinese multiple cancer types. Our revealed the potential targeted therapeutic strategies among non-V600 population with solid tumors should be considered in further study.

Finally, a c-MYC gain, along with a loss of CCND1 and FGFR3, were detected in a patient progressing on a first-line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK-I-resistance mutations in most cases, and could be a valuable approach for therapy decision making.

In addition, GNF-7 and SIJ1227 suppress more strongly migration/invasion of these cancer cells than vemurafenib and PLX8394. Taken together, both GNF-7 and SIJ1227 are much superior to vemurafenib and PLX8394 in terms of capability to inhibit all classes of BRAF mutants.

Legal entity responsible for the study: The authors. Funding: Has not received any funding.