Overcoming Resistance to Drugs Targeting KRAS Mutation

Jiao, Delong; Yang, Shengyu

doi:10.1016/j.xinn.2020.100035

Cited by 56 publications

(55 citation statements)

References 104 publications

(312 reference statements)

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“…In conclusion, KRAS G12C specific inhibitors are a testament to the progress that has been made in targeting an oncogene that was previously considered “undruggable”. Two KRAS G12C inhibitors, adagrasib and sotorasib, have shown efficacy in early clinical trials and further clinical studies are underway [ 27 , 40 ]. Like the downstream targeted therapies that have preceded them, it is clear that G12C inhibitors will induce acquired resistance.…”

Section: Resultsmentioning

confidence: 99%

“…A lack of dependency on KRAS signalling could account for some of the intrinsic resistance noted in pre-clinical models, which may underlie the variable response seen in patients [ 27 , 39 , 40 ]. RAS proteins exert their effects through multiple pathways, including the MAPK/ERK and PI3K/AKT/mTORC1 pathways, although the PI3K pathway is not dependent on RAS alone for activation [ 41 ].…”

Section: Mechanisms Of Resistance To Kras G12cmentioning

confidence: 99%

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Mechanisms of Resistance to KRASG12C Inhibitors

Dunnett-Kane

Nicola

Blackhall

et al. 2021

Cancers

101

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KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of “undruggable”. Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Mechanisms Of Resistance To Kras G12cmentioning

confidence: 99%

Mechanisms of Resistance to KRASG12C Inhibitors

Dunnett-Kane

Nicola

Blackhall

et al. 2021

Cancers

101

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“…As for tumor invasion and metastasis, carcinoma-associated fibroblasts are able to enhance tumor cells migration and invasion via activating the process of specific pathways. For example, as lung cancer maintains the leading cause of cancer-related deaths, IPF has been demonstrated that it increases the risk of lung cancer development by 7–20%, and there are multiple common molecular processes that associated IPF with lung cancer, such as epithelial–mesenchymal transition (EMT), endoplasmic reticulum stress, and abnormal expression of growth factors ( Gu et al, 2018 , 2020a , b ; Ballester et al, 2019 ; Jiao and Yang, 2020 ). In the tissue of myopathies, there is prominent endomysial fibrosis, but little or no inflammation.…”

Section: Introductionmentioning

confidence: 99%

Identification of Common Genes and Pathways in Eight Fibrosis Diseases

Shi

Dang

et al. 2021

Front. Genet.

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Acute and chronic inflammation often leads to fibrosis, which is also the common and final pathological outcome of chronic inflammatory diseases. To explore the common genes and pathogenic pathways among different fibrotic diseases, we collected all the reported genes of the eight fibrotic diseases: eye fibrosis, heart fibrosis, hepatic fibrosis, intestinal fibrosis, lung fibrosis, pancreas fibrosis, renal fibrosis, and skin fibrosis. We calculated the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment scores of all fibrotic disease genes. Each gene was encoded using KEGG and GO enrichment scores, which reflected how much a gene can affect this function. For each fibrotic disease, by comparing the KEGG and GO enrichment scores between reported disease genes and other genes using the Monte Carlo feature selection (MCFS) method, the key KEGG and GO features were identified. We compared the gene overlaps among eight fibrotic diseases and connective tissue growth factor (CTGF) was finally identified as the common key molecule. The key KEGG and GO features of the eight fibrotic diseases were all screened by MCFS method. Moreover, we interestingly found overlaps of pathways between renal fibrosis and skin fibrosis, such as GO:1901890-positive regulation of cell junction assembly, as well as common regulatory genes, such as CTGF, which is the key molecule regulating fibrogenesis. We hope to offer a new insight into the cellular and molecular mechanisms underlying fibrosis and therefore help leading to the development of new drugs, which specifically delay or even improve the symptoms of fibrosis.

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“…Indeed, some specific compounds drugging wild type and oncogenic RAS or selectively drugging only specific mutant KRAS have been discovered and entered in clinical trials testing their efficacy on KRAS direct inhibition [ 17 , 18 , 19 , 20 ]. Nevertheless, these specific approaches also cause drug resistance, making necessary the identification of other strategies to avoid cancer cell adaptation [ 21 , 22 , 23 ]. Therefore, combined treatments able either to enhance the effects of the RAS inhibitors or to avoid the mechanisms of resistance are still needed [ 21 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, these specific approaches also cause drug resistance, making necessary the identification of other strategies to avoid cancer cell adaptation [ 21 , 22 , 23 ]. Therefore, combined treatments able either to enhance the effects of the RAS inhibitors or to avoid the mechanisms of resistance are still needed [ 21 , 24 ]. Indeed, new combined treatments, targeting cell cycle-related pathways, DNA repair related pathways, and metabolic pathways have already been proposed and are currently being tested in preclinical and clinical trials [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

Ricciardiello

Bergamaschi

Vitto

et al. 2021

Cells

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein N-glycosylation, these cells undergo apoptosis significantly more than PDAC cells expressing wild-type KRAS. Importantly, we also show that the combined treatment between FR054 and the pan-RAS inhibitor BI-2852 has an additive negative effect on cell proliferation and survival by means of the suppression of both Akt activity and cyclin D1 expression. Thus, co-inhibition of HBP and oncogenic RAS may represent a novel therapy for PDAC patients.

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Overcoming Resistance to Drugs Targeting KRAS Mutation

Cited by 56 publications

References 104 publications

Mechanisms of Resistance to KRASG12C Inhibitors

Mechanisms of Resistance to KRASG12C Inhibitors

Identification of Common Genes and Pathways in Eight Fibrosis Diseases

Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

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