KRAS mutation: from undruggable to druggable in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Nov. 15, 2021

Abstract Cancer is the leading cause of death worldwide, and its treatment outcomes have been dramatically revolutionised by targeted therapies. As most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding KRAS constantly being updated numerous studies on in initiation progression cancer diseases. However, deemed a challenging therapeutic target, even “undruggable”, after drug-targeting efforts over past four decades. Recently, there surprising advances directly drugs for KRAS, especially (G12C) inhibitors, such as AMG510 (sotorasib) MRTX849 (adagrasib), which obtained encouraging results clinical trials. Excitingly, was first to be approved use this year. This review summarises recent fundamental aspects relationship between mutations tumour immune evasion, new progress targeting particularly (G12C). Moreover, possible mechanisms resistance inhibitors combination therapies are summarised, with view providing best regimen individualised achieving truly precise treatment.

Language: Английский

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Pancreatic cancer: Advances and challenges

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1729 - 1754

Published: April 1, 2023

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. tumors are characterized by a complex microenvironment that orchestrates metabolic alterations supports milieu interactions among various cell types within this niche. In review, we highlight foundational studies driven our understanding these processes. We further discuss recent technological advances continue to expand complexity. posit clinical translation research endeavors will enhance currently dismal survival rate recalcitrant disease.

Language: Английский

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Targeting p53 pathways: mechanisms, structures and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 1, 2023

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. p53 protein transcription factor that can activate expression multiple target genes plays critical roles regulating cell cycle, apoptosis, genomic stability, widely regarded as "guardian genome". Accumulating evidence shown also regulates metabolism, ferroptosis, microenvironment, autophagy so on, all which contribute to suppression. Mutations not only impair its function, but confer oncogenic properties mutants. Since mutated inactivated malignant tumors, it very attractive for developing new anti-cancer drugs. However, until recently, was considered an "undruggable" little progress made with p53-targeted therapies. Here, we provide systematic review diverse molecular mechanisms signaling pathway how mutations impact progression. We discuss key structural features inactivation by mutations. In addition, efforts have therapies, challenges encountered clinical development.

Language: Английский

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The current state of the art and future trends in RAS-targeted cancer therapies

Nature Reviews Clinical Oncology, Journal Year: 2022, Volume and Issue: 19(10), P. 637 - 655

Published: Aug. 26, 2022

Language: Английский

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Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 388(1), P. 44 - 54

Published: Dec. 21, 2022

Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a epidermal growth factor receptor antibody could be effective strategy.In this phase 1-2, open-label, nonrandomized trial, we assigned heavily metastatic cancer to receive adagrasib monotherapy (600 mg orally twice daily) or (at the same dose) combination intravenous cetuximab once week (with initial loading dose 400 per square meter body-surface area, followed by 250 meter) every 2 weeks 500 meter). The primary end points were objective response (complete partial response) and safety.As June 16, 2022, total 44 had received adagrasib, 32 therapy cetuximab, median follow-up 20.1 months 17.5 months, respectively. In group (43 evaluable patients), was reported 19% (95% confidence interval [CI], 8 33). duration 4.3 CI, 2.3 8.3), progression-free survival 5.6 4.1 8.3). combination-therapy (28 46% 28 66). 7.6 5.7 not estimable), 6.9 5.4 8.1). percentage grade 3 4 treatment-related adverse events 34% 16% group. No 5 observed.Adagrasib antitumor G12C, both as cetuximab. more than 6 Reversible common two groups. (Funded Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).

Language: Английский

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Pan-KRAS inhibitor disables oncogenic signalling and tumour growth

Nature, Journal Year: 2023, Volume and Issue: 619(7968), P. 160 - 166

Published: May 31, 2023

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The successful these has development covalent allele-specific inhibitors that trap G12C inactive conformation suppress tumour growth patients1-7. Whether inactive-state selective inhibition can be used therapeutically target non-G12C mutants remains under investigation. Here we report discovery characterization a non-covalent inhibitor binds preferentially with high affinity state while sparing NRAS HRAS. Although limited only few amino acids, evolutionary divergence GTPase domain RAS isoforms was sufficient impart orthosteric allosteric constraints selectivity. blocked nucleotide exchange prevent activation wild-type broad range mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N A146V/T. Inhibition downstream signalling proliferation restricted cancer cells harbouring mutant KRAS, drug treatment suppressed mice, without having detrimental effect on animal weight. Our study suggests oncoproteins cycle between an active are dependent activation. Pan-KRAS inhibitors, such as described here, therapeutic implications merit clinical investigation patients KRAS-driven cancers.

Language: Английский

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Anticancer drug resistance: An update and perspective

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 59, P. 100796 - 100796

Published: Dec. 1, 2021

Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer is based upon a plethora distinct mechanisms. Drug occur in same protein or different proteins; as well pathway parallel pathways, bypassing intercepted signaling. The dilemma clinical oncologist facing not all genomic alterations tumor microenvironment facilitate cell proliferation are known, neither likely to metastasis. For example, common KRas

Language: Английский

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Molecular targeted therapy for anticancer treatment

Experimental & Molecular Medicine, Journal Year: 2022, Volume and Issue: 54(10), P. 1670 - 1694

Published: Oct. 12, 2022

Abstract Since the initial clinical approval in late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served a fundamental backbone precision medicine cancer treatment. These approaches are now used clinically first-line various human cancers. Compared to conventional chemotherapy, have efficient with fewer side effects. However, emergence drug resistance is major drawback therapy, several strategies been attempted improve efficacy by overcoming such resistance. Herein, we summarize current knowledge regarding agents, including classification, brief biology target kinases, mechanisms action, examples perspectives future development.

Language: Английский

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Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer

Cancer Discovery, Journal Year: 2022, Volume and Issue: 13(2), P. 298 - 311

Published: Dec. 6, 2022

Abstract Mutations in the KRAS oncogene are found more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), Gly-to-Asp mutations (KRASG12D) being most common. Here, we tested efficacy a small-molecule KRASG12D inhibitor, MRTX1133, implantable and autochthonous PDAC models an intact immune system. In vitro studies validated specificity potency MRTX1133. vivo, MRTX1133 prompted deep tumor regressions all tested, including complete or near-complete remissions after 14 days. Concomitant cell apoptosis proliferative arrest, drug treatment led to marked shifts microenvironment (TME), changes fibroblasts, matrix, macrophages. T cells were necessary for MRTX1133's full antitumor effect, T-cell depletion accelerated regrowth therapy. These results validate specificity, potency, immunocompetent KRASG12D-mutant models, providing rationale clinical testing platform further investigation combination therapies. Significance: Pharmacologic inhibition cancer system stimulates specific, potent, durable regressions. absence overt toxicity, these suggest that this similar inhibitors should be as potential, high-impact novel therapies PDAC. See related commentary by Redding Grabocka, p. 260. This article is highlighted Issue feature, 247

Language: Английский

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Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

Science, Journal Year: 2022, Volume and Issue: 377(6611), P. 1180 - 1191

Published: Aug. 18, 2022

Drug resistance in cancer is often linked to changes tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated causes of lineage prostate its relationship antiandrogen resistance. We found that initiates an epithelial population defined by mixed luminal-basal phenotype it depends on increased Janus kinase (JAK) fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce dependency observed mice up-regulating luminal gene expression upon JAK FGFR inhibitor treatment. Single-cell analysis confirms presence JAK/STAT (signal transducer activator transcription) signaling a subset metastatic disease, implications for stratifying clinical trials.

Language: Английский

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