Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

Abstract

Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS–RAF–MAPK kinase (MEK)–extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

Shedding light on the shadows: oxidative stress and its pivotal role in prostate cancer progression

“…Moreover, activation of the nuclear factor kappa B pathway by ROS can lead to increased expression of genes promoting the survival of cancer cells, inflammatory cytokines, and growth factors, thus promoting the progression of prostate cancer ( 51 ). Understanding these mechanisms may be crucial for the development of targeted therapies that can inhibit disease progression by blocking ROS-dependent signaling pathways ( 52 ).…”

Tumor biomarkers for diagnosis, prognosis and targeted therapy

“… 303 , 353 Active RAS binds to RAF kinase, which results in RAF dimerization and activation. 354 , 355 RAF proteins possess three isoforms including BRAF, CRAF, and ARAF which share conserved regions of the regulatory domain and kinase domain, 356 and among them, ARAF exhibits the lowest kinase activities. 357 The active RAF dimer phosphorylates and activates MEK1/2 which subsequently phosphorylates and activates ERK1/2, followed by the phosphorylation and activation of downstream effectors and the proliferation of cells.…”

Chemotherapy Resistance in Cancer: Mechanism and Roadmap to Evade Exploring Apoptosis

“…and down-regulation of pro-apoptotic proteins (Bax, Bak, Bid, and Bad) have been observed in cancer cells (Campbell & Tait, 2018;Qian et al, 2022).Furthermore, mutations in pro-and anti-apoptotic proteins can modulate their activity causing apoptosis evasion (Shahar & Larisch, 2020). Activation of PI3K/Akt and MAPK/ERK cell survival pathways can also cause evasion of apoptosis (Bahar et al, 2023;Liu et al, 2020a). Phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated from PI3K recruits Akt to the cell membrane and the phosphorylation at Thr308 and Ser473 residues inhibit pro-apoptotic protein Bad, caspase-9, Forkhead Box O (FoxO) transcription factor (Datta et al, 1997;Jeong et al, 2008;Zhang et al, 2011).…”