Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

Ji, Jingran; Wang, Chongkai; Fakih, Marwan

doi:10.2147/ott.s340392

Cited by 17 publications

(9 citation statements)

References 66 publications

(90 reference statements)

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“…Apart from these investigations into novel monotherapies, there is considerable interest in combining KRAS G12C inhibitors with other targets as a way to either potentiate their clinical effect or counteract the development of resistance. While the addition of anti-EGFR antibodies was one of the earliest studied combinations, concurrently targeting BRAF, MEK, and other downstream steps in the RAS/MAPK signaling pathway holds theoretical promise as well ( 52 ). In vitro and mouse models of lung cancer, for instance, have shown that adding the mTOR inhibitor everolimus to a KRAS G12C inhibitor reduces tumor cell viability ( 53 ).…”

Section: Targeting Krasmentioning

confidence: 99%

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer

Qunaj,

May,

Neugut

et al. 2023

Front. Oncol.

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KRAS G12C mutations are critical in the pathogenesis of multiple cancer types, including non-small cell lung (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal (CRC) cancers. As such, they have increasingly become a target of novel therapies in the management of these malignancies. However, the therapeutic success of KRAS G12C inhibitors to date has been far more limited in CRC and PDAC than NSCLC. In this review, we briefly summarize the biochemistry of KRAS targeting and treatment resistance, highlight differences in the epidemiology of various G12C-mutated cancers, and provide an overview of the published data on KRAS G12C inhibitors for various indications. We conclude with a summary of ongoing clinical trials in G12C-mutant CRC and a discussion of future directions in the management of this disease. KRAS G12C mutation, targeted therapies, colorectal cancer, non-small cell lung cancer, pancreatic cancer, drug development.

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Section: Targeting Krasmentioning

confidence: 99%

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer

Qunaj,

May,

Neugut

et al. 2023

Front. Oncol.

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“…In addition to lung and colorectal cancer, oncogenic KRAS could also facilitate HIF-1α activation and promote pancreatic tumor growth under hypoxic conditions [ 19 ]. Extended to a clinical application, a comparison of the relevance with clinical observations showing that patients with CRC derive less benefit compared with those with NSCLC from a KRAS inhibitor [ 38 ], may indicate that a hypoxia-dependent complex signaling pathway should be taken into consideration in KRAS -mutant cancer research.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of AMG510 Therapy on KRAS-Mutant Non–Small Cell Lung Cancer and Colorectal Cancer Cell Using a 3D Invasive Tumor Spheroid System under Normoxia and Hypoxia

Huang

Zhang

Li³

et al. 2022

Bioengineering

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A 3D tumor spheroid has been increasingly applied in pharmaceutical development for its simulation of the tumor structure and microenvironment. The embedded-culture of a tumor spheroid within a hydrogel microenvironment could help to improve the mimicking of in vivo cell growth and the development of 3D models for tumor invasiveness evaluation, which could enhance its drug efficiency prediction together with cell viability detection. NCI-H23 spheroids and CT-26 spheroids, from a non–small cell lung cancer and colorectal cancer cell line, respectively, together with extracellular matrix were generated for evaluating their sensitivity to AMG510 (a KRASG12C inhibitor) under normoxia and hypoxia conditions, which were created by an on-stage environmental chamber. Results demonstrated that NCI-H23, the KRASG12C moderate expression cell line, only mildly responded to AMG510 treatment in normal 2D and 3D cultures and could be clearly evaluated by our system in hypoxia conditions, while the negative control CT-26 (G12D-mutant) spheroid exhibited no significant response to AMG510 treatment. In summary, our system, together with a controlled microenvironment and imaging methodology, provided an easily assessable and effective methodology for 3D in vitro drug efficiency testing and screenings.

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“…Encorafenib inhibits BRAFV600E and can be explicitly used in treatments related to BRAF mutations. 116 , 117 …”

Section: Significance and Progression Of Personalized Medicinementioning

confidence: 99%

Recent Advancements, Limitations, and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer

Dey

Mitra

Pathak

et al. 2023

Technol Cancer Res Treat

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Due to the heterogeneity of colon cancer, surgery, chemotherapy, and radiation are ineffective in all cases. The genomic profile and biomarkers associated with the process are considered in personalized medicine, along with the patient's personal history. It is based on the response of the targeted therapies to specific genetic variations. The patient's genetic transcriptomic and epigenetic features are evaluated, and the best therapeutic approach and diagnostic testing are identified through personalized medicine. This review aims to summarize all the necessary, updated information on colon cancer related to personalized medicine. Personalized medicine is gaining prominence as generalized treatments are finding it challenging to contain colon cancer cases which currently rank fourth among global cancer incidence while being the fifth largest in total death cases worldwide. In personalized therapy, patients are grouped into specific categories, and the best therapeutic approach is chosen based on evaluating their molecular features. Various personalized strategies are currently being explored in the treatment of colon cancer involving immunotherapy, phytochemicals, and other biomarker-specific targeted therapies. However, significant challenges must be overcome to integrate personalized medicine into healthcare systems completely. We look at the various signaling pathways and genetic and epigenetic alterations associated with colon cancer to understand and identify biomarkers useful in targeted therapy. The current personalized therapies available in colon cancer treatment and the strategies being explored to improve the existing methods are discussed. This review highlights the advantages and limitations of personalized medicine in colon cancer therapy. The current scenario of personalized medicine in developed countries and the challenges faced in middle- and low-income countries are also summarized. Finally, we discuss the future perspectives of personalized medicine in colon cancer and how it could be integrated into the healthcare systems.

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Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

Cited by 17 publications

References 66 publications

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer

Prognostic and therapeutic impact of the KRAS G12C mutation in colorectal cancer

Evaluation of AMG510 Therapy on KRAS-Mutant Non–Small Cell Lung Cancer and Colorectal Cancer Cell Using a 3D Invasive Tumor Spheroid System under Normoxia and Hypoxia

Recent Advancements, Limitations, and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer

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