About this Research Topic
RAS signaling plays an essential role in normal cellular proliferation, while aberrant activation of this pathway is a driver of multiple cancers. KRAS is the most frequently mutated oncogene in human cancers, present in about 30% of cancers, with high frequencies in lung adenocarcinomas (32%), colorectal carcinomas (50%), and pancreatic cancers (95%). Mutations in other RAS genes also contribute to human cancers, for example, NRAS mutations are common in melanoma, while HRAS mutations frequently occur in head and neck cancers. Amplification and activation of non-mutated wild-type (WT) RAS is a feature of other cancers such as esophageal, stomach, ovarian, and testicular cancers and of neurofibromatosis type 1 (NF1).
KRAS-G12C inhibitors have recently received FDA approval, which represent a breakthrough in the development of targeted therapeutic strategies against RAS oncogenic proteins previously considered undruggable. The KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are being used to treat patients with KRAS-G12C-mutated non-small cell lung cancer, although colorectal cancer patients with the same mutation appear to be resistant. Recent research shows that other point mutations in KRAS can be targeted by small-molecule inhibitors. KRAS inhibitors have shown promising results in clinical trials. For example, Mirati Therapeutics developed a KRAS-G12D inhibitor, MRTX1133, which showed significant preclinical antitumor activity in KRAS-G12D-tumor bearing mice, especially pancreatic ductal adenocarcinoma. However, major limitations for allele-specific KRAS inhibitors are the heterogeneity of KRAS mutations, coexistence of multiple KRAS mutations, and resistance that is caused by the emergence of new KRAS mutations or from activation of co-expressed wild-type RAS isozymes by upstream signaling pathways. As such, pan-RAS inhibitors, and inhibitors of SOS1 are being developed that show promise in preclinical studies and the potential for greater efficacy or reduced potential for resistance. Alternatively, combining a RAS inhibitor with other drugs might overcome resistance.
We are announcing this Research Topic of Frontiers in Oncology devoted to investigations of the mechanisms, selectivity, efficacy, toxicity, and drug resistance of these and other novel RAS-targeted inhibitors for the treatment and hopefully cure of cancer. We are especially interested in articles describing therapeutic advances using RAS-targeted inhibitors administered alone or in combination with other molecularly targeted drugs, chemotherapy, radiation therapy, or immunotherapy.
Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) will not be accepted in any of the sections of Frontiers in Oncology.
KRAS-G12C inhibitors have recently received FDA approval, which represent a breakthrough in the development of targeted therapeutic strategies against RAS oncogenic proteins previously considered undruggable. The KRAS-G12C inhibitors sotorasib (AMG510) and adagrasib (MRTX849) are being used to treat patients with KRAS-G12C-mutated non-small cell lung cancer, although colorectal cancer patients with the same mutation appear to be resistant. Recent research shows that other point mutations in KRAS can be targeted by small-molecule inhibitors. KRAS inhibitors have shown promising results in clinical trials. For example, Mirati Therapeutics developed a KRAS-G12D inhibitor, MRTX1133, which showed significant preclinical antitumor activity in KRAS-G12D-tumor bearing mice, especially pancreatic ductal adenocarcinoma. However, major limitations for allele-specific KRAS inhibitors are the heterogeneity of KRAS mutations, coexistence of multiple KRAS mutations, and resistance that is caused by the emergence of new KRAS mutations or from activation of co-expressed wild-type RAS isozymes by upstream signaling pathways. As such, pan-RAS inhibitors, and inhibitors of SOS1 are being developed that show promise in preclinical studies and the potential for greater efficacy or reduced potential for resistance. Alternatively, combining a RAS inhibitor with other drugs might overcome resistance.
We are announcing this Research Topic of Frontiers in Oncology devoted to investigations of the mechanisms, selectivity, efficacy, toxicity, and drug resistance of these and other novel RAS-targeted inhibitors for the treatment and hopefully cure of cancer. We are especially interested in articles describing therapeutic advances using RAS-targeted inhibitors administered alone or in combination with other molecularly targeted drugs, chemotherapy, radiation therapy, or immunotherapy.
Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) will not be accepted in any of the sections of Frontiers in Oncology.
Keywords: Therapy of RAS-mutant cancers, RAS-targeted inhibitors, Resistance mechanisms, Combination treatment strategies, Preclinical and clinical development, Toxicity
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
