BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale

Abstract

BRAF V600 mutations have been found in 1–2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50–80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions.

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

“…SHP2 is a critical regulator of RAS MAPK pathway and SHP2 inhibitors have activity in cancers with KRAS mutations and BRAF mutations [ 87 ]. SHP2 inhibitors could target cancer cells, T lymphocytes, and macrophages simultaneously, and, thereby, could have significant activity in conjunction with anti-PD-1 and anti-PD-L1 antibodies ( Table 2 ) [ 88 ].…”

A Rare p.T599dup BRAF Mutant NSCLC in a Non-Smoker

“…Non-V600 BRAF mutations, however, are largely seen in lung cancers and melanomas [ 1 , 3 , 4 ]. BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins, such as rapidly accelerated fibrosarcoma (RAF) [ 1 , 5 ]. This makes them susceptible to targeted therapies with RAF inhibitors [ 1 , 5 ].…”

“…BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins, such as rapidly accelerated fibrosarcoma (RAF) [ 1 , 5 ]. This makes them susceptible to targeted therapies with RAF inhibitors [ 1 , 5 ]. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations [ 1 , 5 ].…”

“…This makes them susceptible to targeted therapies with RAF inhibitors [ 1 , 5 ]. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations [ 1 , 5 ]. While several approaches have been investigated to overcome the limitations of RAF inhibitors, such as use of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) inhibitors or combination of MEK and RAF inhibitors, none of them have been proven to have a superior efficacy for low kinase activity non-V600 BRAF tumors [ 1 ].…”

“…We would like to present a case of a BRAF mutated non-small cell lung cancer (NSCLC), an exceptionally rare form of lung cancer found only in one to two percent of patients carrying an NSCLC diagnosis and usually affecting patients who are former or current smokers [ 5 , 6 ]. The presented case illustrates an extremely rare variant of BRAF p.T599dup mutation in a non-smoker that responded to targeted combination therapy with RAF and MEK inhibitors.…”