Precision Therapy in RAS Mutant Colorectal Cancer

Dienstmann, Rodrigo; Connor, Kate; Byrne, Annette T.; Fridman, Wolf‐Herman; Lambrechts, Diether; Sadanandam, Anguraj; Trusolino, Livio; Prehn, Jochen H M; Tabernero, Josep; Kölch, Walter

doi:10.1053/j.gastro.2019.12.051

Cited by 41 publications

(27 citation statements)

References 27 publications

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“…27,28 KRAS G12C is identified in approximately 4% of CRCs. 12 Its oncogenic activity is linked to impaired GAP-mediated hydrolysis, resulting in marked predominance of the GTPbound active state. However, KRAS G12C preserves peculiar near-wild-type (WT) intrinsic GTPase activity and thus slight GTP-to-GDP cycling ability, differently from other KRAS codon mutations.…”

Section: Ras Direct Inhibitors: New Perspectives Limited To the Kras G12c Mutationmentioning

confidence: 99%

“…11 Indeed, around 40% of CRC harbors KRAS mutations plus an additional 4% NRAS mutations (and a negligible <1% prevalence of HRAS mutations), with >95% of them occurring in KRAS G12, G13, or Q61 codons. 4,11,12 G12 hotspot mutations account for around 68% of KRAS mutations in mCRC, most frequently G12D (~45%), G12V (~31%), and G12C (~11%) in MSS tumors, and predominantly G12D in MSI ones (Figure 1 and Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop. 2021.100156).…”

Section: Introductionmentioning

confidence: 99%

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Strategies to tackle RAS-mutated metastatic colorectal cancer

et al. 2021

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The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRAS G12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRAS G12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRAS G12C . In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.

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Section: Ras Direct Inhibitors: New Perspectives Limited To the Kras G12c Mutationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Strategies to tackle RAS-mutated metastatic colorectal cancer

et al. 2021

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“…Somatic mutations in MAPK were shown to be correlated with poor survival after CRC diagnosis in a study by Barault et al KRAS and NRAS activating missense mutations have been reported in 40% and 4% of CRC, respectively; up to 95% of mutations involve one of three major hotspots (residues G12, G13, and Q61) [83]. As for elderly patients, a different incidence of KRAS mutation has been reported according to the microsatellite status of the tumor; indeed, in this population, KRAS mutation seems to be more frequent in the case of microsatellite-stable MSS CRC, especially in males, whereas it seems to be lower in microsatellite-unstable tumors or with high mutational burden [84,85].…”

Section: Mapk-ras/raf/mek/erk Pathwaymentioning

confidence: 99%

Molecular-Biology-Driven Treatment for Metastatic Colorectal Cancer

Lai

Liscia

Donisi

et al. 2020

Cancers

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Background: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. Methods: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. Results: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. Conclusion: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.

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“…increased glutaminolysis and lipidogenesis, 13%); and (4) CMS4 (associated with epithelial-mesenchymal transition, 23%) [23]. CMS3 is particularly relevant for this review as it shows a clear overrepresentation of KRAS mutations (80%) [24].…”

Section: Molecular Carcinogenic Pathways and Subtypes In Crcmentioning

confidence: 99%

Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

Ternet

Kiel

2021

Cell Commun Signal

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The intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer.

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Precision Therapy in RAS Mutant Colorectal Cancer

Cited by 41 publications

References 27 publications

Strategies to tackle RAS-mutated metastatic colorectal cancer

Strategies to tackle RAS-mutated metastatic colorectal cancer

Molecular-Biology-Driven Treatment for Metastatic Colorectal Cancer

Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

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