The Evolution of BRAF Activation in Non-Small-Cell Lung Cancer

Abstract

Non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer, of which approximate 4% had BRAF activation, with an option for targeted therapy. BRAF activation comprises of V600 and non-V600 mutations, fusion, rearrangement, in-frame deletions, insertions, and co-mutations. In addition, BRAF primary activation and secondary activation presents with different biological phenotypes, medical senses and subsequent treatments. BRAF primary activation plays a critical role in proliferation and metastasis as a driver gene of NSCLC, while secondary activation mediates acquired resistance to other targeted therapy, especially for epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). Treatment options for different activation of BRAF are diverse. Targeted therapy, especially two-drug combination therapy, is an important option. Besides, immune checkpoint inhibitors (ICIs) would be another option since BRAF activation would be a positive biomarker of tumor response of ICIs therapy. To date, no high level evidences support targeted therapy or immunotherapy as prioritized recommendation. After targeted therapy, the evolution of BRAF includes the activation of the upstream, downstream and bypass pathways of BRAF. In this review, therapeutic modalities and post-therapeutic evolutionary pathways of BRAF are discussed, and future research directions are also provided.

Case report: BRAF A598-T599insV mutation as a potential resistance mechanism to alectinib in ALK-rearranged lung adenocarcinoma

“…In our patient, in the absence of an ALK mutation but presence of a BRAF A598_T599insV mutation at progression on alectinib, we proposed participation in a phase 1b clinical trial evaluating a BRAF and a MEK inhibitor in BRAF- and KRAS-mutated NSCLC and NRAS-mutated melanoma instead of a treatment with lorlatinib. BRAF mutations are found in 1.5-3.5% of NSCLCs at diagnosis, almost exclusively in adenocarcinoma, and are responsible for the MAPK/ERK pathway activation leading to tumor development and progression ( 14 ). Half of BRAF -mutated NSCLCs have a BRAF V600E mutation, which is more frequent in light/never-smokers and, at diagnosis, is mutually exclusive with other oncogenic drivers such as ALK rearrangement.…”

Advances in Genomic Data and Biomarkers: Revolutionizing NSCLC Diagnosis and Treatment

“…These include the combination of BRAF inhibitors with MEK inhibitors to block multiple signaling pathways, the use of EGFR inhibitors in combination with BRAF inhibitors, and the combination of targeted therapies with immunotherapy to enhance the immune response against tumor cells. Although significant progress has been made in the treatment of resistance to BRAF inhibition in NSCLC, further research is still needed to fully understand the resistance mechanisms and develop more effective therapeutic strategies [ 27 , 28 ].…”

Therapeutic strategies for BRAF mutation in non-small cell lung cancer: a review

“…KRAS co-mutation was given Dabrafenib-Trametinib therapy ( 59 ). The use of immunotherapy, specifically immune checkpoint inhibitors (ICIs), is more and more being used as a solution to BRAF co-mutations ( 63 ). More research is needed to study the clinical implications of the use of multi-targeted chemotherapy drugs and immune therapy in concurrent mutations.…”