RAF and MEK Inhibitors in Non-Small Cell Lung Cancer

Abstract

Lung cancer, despite recent advancements in survival rates, represents a significant global health burden. Non-small cell lung cancer (NSCLC), the most prevalent type, is driven largely by activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) and receptor tyrosine kinases (RTKs), and less in v-RAF murine sarcoma viral oncogene homolog B (BRAF) and mitogen-activated protein-kinase kinase (MEK), all key components of the RTK-RAS-mitogen-activated protein kinase (MAPK) pathway. Learning from melanoma, the identification of BRAFV600E substitution in NSCLC provided the rationale for the investigation of RAF and MEK inhibition as a therapeutic strategy. The regulatory approval of two RAF-MEK inhibitor combinations, dabrafenib-trametinib, in 2017, and encorafenib-binimetinib, in 2023, signifies a breakthrough for the management of BRAFV600E-mutant NSCLC patients. However, the almost universal emergence of acquired resistance limits their clinical benefit. New RAF and MEK inhibitors, with distinct biochemical characteristics, are in preclinical and clinical development. In this review, we aim to provide valuable insights into the current state of RAF and MEK inhibition in the management of NSCLC, fostering a deeper understanding of the potential impact on patient outcomes.

Keywords: BRAF inhibitors; BRAFV600E; MAPK pathway; MEK inhibitors; lung cancer; non-small cell lung cancer; targeted therapies.

Figure 1

The RTK/RAS/MAPK pathway, its key components and mutations in lung cancer and the different categories of RAF inhibitors based on their distinct structural properties. RTK, receptor tyrosine kinase; SHP2, Src homology 2 domain-containing phosphatase 2; SOS1, son of sevenless homolog; KRAS, Kirsten rat sarcoma viral oncogene homolog; GDP, guanosine diphosphate; GTP, guanosine triphosphate; BRAF, v-RAF murine sarcoma viral oncogene homolog B; MEK, mitogen-activated protein-kinase kinase; ERK, extracellular signal-regulated kinase; AP-1, activator protein-1; c-MYC, cellular Myelocytomatosis oncogene; ELK-1, ETS like-1; NF1, neurofibromin 1; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, c-ros oncogene-1; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2; RET, rearranged during transfection; NTRK, neurotrophic tropomyosin receptor kinase. This figure was created using the tools provided by BioRender.com (accessed on 10 April 2024).

Figure 2

BRAF and MEK inhibitors under clinical evaluation in combination, or not, with various targeted therapies for lung cancer. RTK, receptor tyrosine kinase; SHP2, Src homology 2 domain-containing phosphatase 2; SOS1, son of sevenless homolog; KRAS, Kirsten rat sarcoma viral oncogene homolog; GDP, guanosine diphosphate; GTP, guanosine triphosphate; RAF, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein-kinase kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; PIP2/3, phosphatidylinositol 2/3; PTEN, phosphatase and tensin homolog; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; ROS1, c-ros oncogene-1; MET, hepatocyte growth factor receptor; ALK, anaplastic lymphoma kinase; KIT, tyrosine-protein kinase kit; PDGFR, platelet-derived growth factor receptor; TRK, tropomyosin receptor kinase; VEGFR, vascular endothelial growth factor receptor; RET, rearranged during transfection; FGFR, fibroblast growth factor receptor; SMO, smoothened; PD-L1, programmed death-ligand 1; PD-1, programmed cell death protein 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; LAG-3, lymphocyte-activation gene 3; TIGIT, T cell immunoreceptor with Ig and ITIM domains; FAK, focal adhesion kinase; SRC, proto-oncogene tyrosine-protein kinase; ULK1/2, unc-51-like kinase 1/2; CDK4/6, cyclin-dependent kinase 4/6; WEE-1, Wee1-like protein kinase; ATR, ataxia telangiectasia and Rad3-related protein. This figure was created using the tools provided by BioRender.com (accessed on 10 April 2024).