Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers

Abstract

The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by Ras genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.

Mesonephric-like Adenocarcinoma of the Ovary: Clinicopathological and Molecular Characteristics

“…KRAS mutation constitutively results in the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which subsequently activates downstream substrates, leading to the expression of genes involved in cellular proliferation, differentiation, and survival. As targeted inhibitors of the MAPK pathway have been approved to treat several types of KRAS -mutated carcinoma [ 44 ], it is worth investigating the therapeutic significance of MAPK inhibitors for patients with MLA. In fact, the effect on growth suppression of MAPK pathway inhibition in ovarian carcinoma cells was more profound in tumors harboring KRAS mutation than in KRAS wild-type tumors [ 45 ].…”

Investigation of the apoptosis‐inducing effect of docetaxel by comprehensive LC–MS–based metabolomics and network pharmacology approaches

“…Several mechanisms have been demonstrated the anti‐apoptotic effect of the PI3K–Akt–mTOR signal transduction pathway, namely, regulating the activity of Bcl‐2 family members and transcription factor nuclear factor‐kappa B (NF‐κB), and inhibiting the activation of aspartate‐specific cysteine protease family members, the activity of GSK3, the expression of pro‐apoptotic genes, mitochondria from releasing cytochrome c, and activity of the TRAIL (TNF‐related apoptosis‐inducing ligand) receptor (Akbarzadeh et al, 2021; Kaboli et al, 2021; Peng et al, 2022; Sun et al, 2021; Yu et al, 2021). The MAPK signaling pathway exists in many cells across almost all the organisms, and includes ERKs, JNKs, and p38 (Dillon et al, 2021). ERKs are mainly related to cell proliferation and differentiation (Pashirzad et al, 2021; Sugiura et al, 2021).…”

“…Glucose is one of the main members in the glycol- (Akbarzadeh et al, 2021;Kaboli et al, 2021;Peng et al, 2022;Sun et al, 2021;Yu et al, 2021). The MAPK signaling pathway exists in many cells across almost all the organisms, and includes ERKs, JNKs, and p38 (Dillon et al, 2021). ERKs are mainly related to cell proliferation and differentiation (Pashirzad et al, 2021;Sugiura et al, 2021).…”

Targeting Cancer Cell Signaling Using Precision Oncology Towards a Holistic Approach to Cancer Therapeutics

“…Growth factor receptors, such as the TGF-β receptors EGFR, VEGFR, PDGFR, FGFR, and IG-IR, can all activate RAS and downstream RAF and MEK. Ras proteins act as molecular switches that control the activation and regulation of related pathways that are responsible for numerous cell behaviors [62]. The study with selected inhibitors against the targets in this cascade has shown positive results, such as growth inhibition, anti-angiogenesis, and suppressed metastasis in cancer cell lines and animal models.…”