Emerging strategies to target RAS signaling in human cancer therapy DOI Creative Commons
Kun Chen, Yalei Zhang, Ling Qian

et al.

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: July 23, 2021

RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, around 19% of patients with cancer harbor mutations. Cells harboring tend to undergo malignant transformation exhibit phenotypes. The mutational status correlates clinicopathological features patients, such as mucinous type poor differentiation, well response anti-EGFR therapies in certain types human cancers. Although protein had been considered a potential target for tumors mutations, it was once referred undruggable due consecutive failure discovery inhibitors. However, recent studies on structure, signaling, function have shed light development RAS-targeting drugs, especially approval Lumakras (sotorasib, AMG510) treatment KRAS

Language: Английский

Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor DOI
Jill Hallin, Vickie Bowcut, Andrew Calinisan

et al.

Nature Medicine, Journal Year: 2022, Volume and Issue: 28(10), P. 2171 - 2182

Published: Oct. 1, 2022

Language: Английский

Citations

299
Sotorasib in KRAS p.G12C–Mutated Advanced Pancreatic Cancer DOI Open Access
John H. Strickler, Hironaga Satake, Thomas J. George

et al.

New England Journal of Medicine, Journal Year: 2022, Volume and Issue: 388(1), P. 33 - 43

Published: Dec. 21, 2022

KRAS p.G12C mutation occurs in approximately 1 to 2% of pancreatic cancers. The safety and efficacy sotorasib, a G12C inhibitor, previously treated patients with p.G12C–mutated cancer are unknown.

Language: Английский

Citations

280
Pan-KRAS inhibitor disables oncogenic signalling and tumour growth DOI Creative Commons
Dong-Sung Kim, Lorenz Herdeis, Dorothea Rudolph

et al.

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

Citations

269
Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status DOI Creative Commons
Biagio Ricciuti, Kathryn C. Arbour, W. Marston Linehan

et al.

Journal of Thoracic Oncology, Journal Year: 2021, Volume and Issue: 17(3), P. 399 - 410

Published: Nov. 3, 2021

Language: Английский

Citations

259
Rational combinations of targeted cancer therapies: background, advances and challenges DOI
Haojie Jin, Liqin Wang, René Bernards

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 22(3), P. 213 - 234

Published: Dec. 12, 2022

Language: Английский

Citations

249
Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies DOI Creative Commons
Md Entaz Bahar, Hyun Joon Kim, Deok Ryong Kim

et al.

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

Published: Dec. 18, 2023

Metastatic dissemination of solid tumors, a leading cause cancer-related mortality, underscores the urgent need for enhanced insights into molecular and cellular mechanisms underlying metastasis, chemoresistance, mechanistic backgrounds individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is mitogen-activated protein kinase (MAPK) pathway, encompassing RAS-RAF-MAPK (MEK)-extracellular signal-related (ERK) pathway. RAF primary mediator MAPK responsible sequential activation downstream targets, such as MEK transcription factor ERK, which control numerous physiological processes, including organism development, cell cycle control, proliferation differentiation, survival, death. Defects in this associated with diseases cancer. (RAFi) combined blockers represent an FDA-approved therapeutic strategy RAF-mutant cancers, melanoma, non-small lung carcinoma, thyroid However, development therapy resistance cancer cells remains important barrier. Autophagy, intracellular lysosome-dependent catabolic recycling process, plays critical role RAFi Thus, targeting autophagy could be novel treatment strategies cancers. In review, we delve deeper surrounding tumorigenesis RAFi-resistance. Furthermore, explore discuss ongoing next-generation profiles. Additionally, review sheds light on functional interplay between RAF-targeted therapies

Language: Английский

Citations

248
Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer DOI Creative Commons
Samantha B. Kemp, Noah Cheng, Nune Markosyan

et al.

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

Citations

225
The Drug-Dosing Conundrum in Oncology — When Less Is More DOI
Mirat Shah, Atiqur Rahman, Marc R. Theoret

et al.

New England Journal of Medicine, Journal Year: 2021, Volume and Issue: 385(16), P. 1445 - 1447

Published: Oct. 9, 2021

Doses and schedules of oncology drugs are sometimes inadequately characterized before registration trials. The “more is better” paradigm still used for dose selection, despite the recognition that targeted therapies require alternative approaches to optimization.

Language: Английский

Citations

214
Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants DOI Creative Commons
Marco H. Hofmann, Daniel Gerlach, Sandra Misale

et al.

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(4), P. 924 - 937

Published: Jan. 19, 2022

KRAS is the most frequently mutated oncogene, harboring mutations in approximately one seven cancers. Allele-specific KRASG12C inhibitors are currently changing treatment paradigm for patients with KRASG12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive allele has fueled drug discovery efforts all mutants. Pan-KRAS drugs have potential to address broad patient populations, including KRASG12D-, KRASG12V-, KRASG13D-, KRASG12R-, KRASG12A-mutant or wild-type-amplified cancers, as well cancers acquired resistance inhibitors. Here, we review actively pursued allele-specific pan-KRAS inhibition strategies their utility. Mutant-selective target fraction (approximately 13.6%) KRAS-driven A arsenal needed comprehensively conquer Conceptually, foresee two future classes medicines: mutant-selective targeting individual variant alleles therapeutics range alterations.

Language: Английский

Citations

206
Targeted therapy in advanced non-small cell lung cancer: current advances and future trends DOI Creative Commons
Umair Majeed, Rami Manochakian, Yujie Zhao

et al.

Journal of Hematology & Oncology, Journal Year: 2021, Volume and Issue: 14(1)

Published: July 8, 2021

Abstract Lung cancer remains the leading cause of cancer-related mortality in both men and women US worldwide. Non-small cell lung is most common variety accounting for 84% cases. For a subset patients with actionable mutations, targeted therapy continues to provide durable responses. Advances molecular immunohistochemical techniques have made it possible usher into era personalized medicine, patient getting individualized treatment based on these markers. This review summarizes recent advances advanced NSCLC therapy, focusing first-in-human early phase I/II clinical trials disease. We divided our discussion different topics agents' mechanisms action. article aimed be current available upcoming options. will also summarize currently trial at end each section.

Language: Английский

Citations

198