Targeting KRAS in Cancer: Promising Therapeutic Strategies

Mustachio, Lisa Maria; Chelariu-Raicu, Anca; Székvölgyi, Lóránt; Roszik, Jason

doi:10.3390/cancers13061204

Cited by 54 publications

(32 citation statements)

References 86 publications

(118 reference statements)

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“…In addition, the heterogeneity of KRAS mutations results in a variety of different diseases, which hinders the finding of a unique common therapy to address all of them. Thus, while KRAS G12C specific inhibitors have proven efficacy against their target, many other therapeutic strategies are currently under development for those KRAS mutant tumors with no druggable genetic alteration ( 47 ). Clinical trials addressed to KRAS mutant NSCLC non specific for KRAS G12C are listed in Table 1 .…”

Section: Targeting Kras Beyond Kras G12c Mutationsmentioning

confidence: 99%

Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

Cucurull¹,

Notario²,

Sanchez-Cespedes³

et al. 2022

Front. Oncol.

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Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was considered “undruggable” for decades, specific KRAS G12C covalent inhibitors have recently emerged, although their promising results are limited to a subset of patients. Several other drugs targeting KRAS activation and downstream signaling pathways are currently under investigation in early-phase clinical trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes different responses to therapies. This review describes the molecular characterization of KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.

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Section: Targeting Kras Beyond Kras G12c Mutationsmentioning

confidence: 99%

Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

Cucurull¹,

Notario²,

Sanchez-Cespedes³

et al. 2022

Front. Oncol.

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“…RAS proteins are small eukaryotic GTPases that cycle back and forth between the GDP-bound inactive state and the GTP-bound active state. The KRAS gene can simultaneously harbor multiple mutations that can potentiate tumor-promoting activity in several human cancers; thus, it is necessary to utilize a new therapeutic strategy to inhibit this oncoprotein and therefore the development of cancer ( Mustachio et al, 2021 ). However, the RAS oncogene is particularly difficult to target with specific therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…KRAS is the most frequently mutated RAS family member that can potentiate tumor-promoting activity. These KRAS alterations have been identified in 25% of all cancers, such as blood, breast, colorectal, gynecological, lung, prostate, and pancreatic cancer, in which some cancers, pancreatic cancer (90%), colorectal cancer (52%), and lung adenocarcinoma (32%) have extremely high mutation rates ( Mustachio et al, 2021 ).…”

Section: Activities Of Polyphenols In Relevant Cancer-driving Signaling Pathwaysmentioning

confidence: 99%

Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways

2021

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Polyphenols constitute an important group of natural products that are traditionally associated with a wide range of bioactivities. These are usually found in low concentrations in natural products and are now available in nutraceuticals or dietary supplements. A group of polyphenols that include apigenin, quercetin, curcumin, resveratrol, EGCG, and kaempferol have been shown to regulate signaling pathways that are central for cancer development, progression, and metastasis. Here, we describe novel mechanistic insights on the effect of this group of polyphenols on key elements of the signaling pathways impacting cancer. We describe the protein modifications induced by these polyphenols and their effect on the central elements of several signaling pathways including PI3K, Akt, mTOR, RAS, and MAPK and particularly those affecting the tumor suppressor p53 protein. Modifications of p53 induced by these polyphenols regulate p53 gene expression and protein levels and posttranslational modifications such as phosphorylation, acetylation, and ubiquitination that influence stability, subcellular location, activation of new transcriptional targets, and the role of p53 in response to DNA damage, apoptosis control, cell- cycle regulation, senescence, and cell fate. Thus, deep understanding of the effects that polyphenols have on these key players in cancer-driving signaling pathways will certainly lead to better designed targeted therapies, with less toxicity for cancer treatment. The scope of this review centers on the regulation of key elements of cancer signaling pathways by the most studied polyphenols and highlights the importance of a profound understanding of these regulations in order to improve cancer treatment and control with natural products.

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“…1 Mutation in the Kirsten rat sarcoma viral oncogene homolog (KRAS), which can potentiate the tumorpromoting activity, is one of the most common carcinogenic events in endodermal cancer. 2 Actually, KRAS mutations have been identified predominantly in lung (approximately 25% of cases), pancreatic (about 95% of case), and colorectal (approximately 35% of cases) cancer. 3,4 In KRAS mutated tumors, 80% of carcinogenic mutations occur in codon 12, and the most popular mutation sites are KRAS (G12D), KRAS (G12V) and KRAS (G12C).…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics

Xuan

et al. 2022

Analyst

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Targeting KRAS in Cancer: Promising Therapeutic Strategies

Cited by 54 publications

References 86 publications

Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways

Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics

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