Molecular mechanism and clinical outcome of non-small cell lung cancer patients with high BRAF expression

Non-small cell lung cancer (NSCLC) is a genetically heterogeneous disease, with several distinct oncogenic alterations having been characterized. One such subpopulation of lung cancers is BRAF-mutated lung cancer, which constitutes approximately 4% of advanced NSCLC (1,2). The most prevalent BRAF mutations, BRAF V600E mutations, are present in approximately 2% of NSCLC (2,3). These mutations engender activation of the RAF-MEK-ERK (MAPK) pathway, leading to cell proliferation and growth. NSCLC with BRAF V600E mutations and selected non-V600 mutations respond to the treatment of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), while immune checkpoint inhibitors (ICI)-based regimens or chemotherapy, including platinum-based doublet chemotherapy, demonstrate modest efficacy against these BRAF alterations (4-10). Despite the lack of comprehensive studies on the clinical implications of BRAF amplification in tumor development and progression, de novo BRAF amplification has been reported to be 0.1% of NSCLC in American Association for Cancer Research (AACR) Project Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) cohort, and it has been linked to resistance to RTK/RAS/RAF/MEK inhibitors (11-16).

There are three functional classes of BRAF mutations (17-19). Class I BRAF mutations, which operate as monomers independently of RAS activation, result in elevated ERK activation and subsequent negative feedback inhibition of upstream signaling. This class includes BRAF V600E mutations. Class II BRAF mutations, which are RAS-independent and form mutant-mutant BRAF dimers, elicit robust ERK activation and negative feedback inhibition of upstream signaling. Class III BRAF mutations exhibit augmented binding to RAS and CRAF, signaling as mutant BRAF-wild-type (WT) CRAF dimers. They amplify downstream signaling from RAS and thus necessitate upstream activation to enhance ERK signaling, either through genomic alterations (such as RAS mutations or NF1 loss) or through receptor tyrosine kinase (RTK) signaling.

In the accompanying article, Dora et al. demonstrate that a substantial proportion of patients with lung adenocarcinoma (LUAD), namely 73% (47/64), exhibited high levels of WT BRAF RNA across all tumor stages (20). This high expression was associated with never-smoker status, tumor necrosis, low programmed death ligand 1 (PD-L1) expression in immune cells, and poor prognosis to chemotherapy (platinum-based doublet). The gene’s protein product was detected in 80% (8/10) samples from the Human Protein Atlas database using immunohistochemistry (IHC), with moderate or strong staining intensity. The negative prognostic role of high BRAF RNA expression was also confirmed in The Cancer Genome Atlas (TCGA) cohort of LUAD patients (n=318). This study aligns with previous TCGA analyses, which showed that metastatic lesions of LUAD exhibited significantly higher BRAF expression compared to corresponding adjacent normal tissues (14). Furthermore, in the context of papillary thyroid carcinoma, previous TCGA analysis indicated that higher BRAF RNA expression was associated with more aggressive tumor features, including higher tumor stage and the presence of extrathyroidal extension, regardless of BRAF mutational status (21).

The authors noted that the prevalence of LUAD patients with high BRAF expression (73%, 47/64) could not be attributed to BRAF mutations (20), given that only approximately 4% of NSCLC harbor BRAF mutations (1). BRAF amplification could be ruled out as a potential explanation because it is a rare population, 0.1% of NSCLC (12,14,16). Oncogenic alterations in RTK or RAS proteins (such as KRAS, NRAS, and HRAS) are known to activate the MAPK signaling pathway, and we hypothesized these alterations might drive elevated BRAF RNA expression as an aberrant downstream pathway (Figure 1). The proportion of the high BRAF expression group (73%) in this cohort was comparable to that of patients with oncogenic RTK or RAS alterations (75%) in LUAD from MSK-IMPACT Clinical Sequencing Cohort (KRAS, 30%; EGFR, 30%; HER2, 4%; ALK, 4%; MET, 3%; RET, 2%; ROS1, 2%; total, 75%, data from cBio cancer genomics portal) (22). Additionally, never smokers demonstrated significantly higher BRAF expression than current smokers and ex-smokers, suggesting the association between higher BRAF expression and frequent oncogenic RTK or RAS alterations in never smokers. Despite the lack of genomic analysis in this study, the poor prognosis associated with the high BRAF expression group in this cohort and the TCGA cohort may be due to the absence of potential targeted therapies for patients with various driver alterations in RTK or RAS. Most patients in this cohort received platinum-based doublet therapy, thus missing the opportunity for targeted therapies such as osimertinib for EGFR-mutated lung cancer and alectinib for ALK-rearranged lung cancer. If our hypothesis is correct, targeting the overexpressed BRAF pathway would involve inhibiting the upstream activation pathway with RAS inhibitors or RTK inhibitors. A more extensive examination of BRAF RNA expression, RTK-RAS-RAF-MEK-ERK pathway alterations, and clinical prognostic implications is necessary to discern the underlying mechanism behind the prevalent proportion of patients with high BRAF expression and their associated inferior prognosis.

Figure 1 Hypothesis of association between high BRAF expression and RTK/RAS driver alterations in lung adenocarcinoma. LUAD, lung adenocarcinoma.

The relationship between genetic heterogeneity and prognostication has been analyzed in the field of lung cancer; however, the relationship between genotypic and phenotypic heterogeneity and prognostication remains inadequately understood. Most of the consequences of genetic and cytogenetic modifications will influence gene expression through aberrant transcription, epigenetic regulation, and cellular signaling. The vehicle by which driver mutations give rise to carcinogenesis is transcription, facilitated through a labyrinthine cellular signaling circuitry that links genomic alterations to the clinical phenotype of cancers and their prognosis (23). A more comprehensive understanding of driver mutations and differential RNA expression with clinical outcomes beyond BRAF expression is imperative.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Lung Cancer Research. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-103/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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