EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer DOI Open Access
Vito Amodio, Rona Yaeger, Pamela Arcella

et al.

Cancer Discovery, Journal Year: 2020, Volume and Issue: 10(8), P. 1129 - 1139

Published: May 19, 2020

Most patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas colorectal bearing the same mutation rarely respond. To investigate cause of limited efficacy inhibitors in cancer, we examined effects AMG510 G12C lines. Unlike NSCLC lines, models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In inhibition induces higher phospho-ERK rebound than cells. Although upstream several RTKs interferes blockade, identify EGFR signaling as dominant mechanism resistance inhibitors. The combinatorial targeting is highly effective cells patient-derived organoids xenografts, suggesting a novel therapeutic strategy treat cancer. SIGNIFICANCE: lineage-specific. RTK dependency kinetics responsible for sensitivity or should be concomitantly inhibited overcome blockade tumors.See related commentary by Koleilat Kwong, p. 1094.This article highlighted This Issue feature, 1079.

Language: Английский

Targeting apoptosis in cancer therapy DOI
Benedito A. Carneiro, Wafik S. El‐Deiry

Nature Reviews Clinical Oncology, Journal Year: 2020, Volume and Issue: 17(7), P. 395 - 417

Published: March 23, 2020

Language: Английский

Citations

1913
PROTAC targeted protein degraders: the past is prologue DOI Open Access
Miklós Békés, David R. Langley, Craig M. Crews

et al.

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(3), P. 181 - 200

Published: Jan. 18, 2022

Language: Английский

Citations

1824
Lung cancer DOI
Alesha Thai, Benjamin Solomon, Lecia V. Sequist

et al.

The Lancet, Journal Year: 2021, Volume and Issue: 398(10299), P. 535 - 554

Published: July 21, 2021

Language: Английский

Citations

1654
Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy DOI Creative Commons
Pranavi Koppula, Li Zhuang, Boyi Gan

et al.

Protein & Cell, Journal Year: 2020, Volume and Issue: 12(8), P. 599 - 620

Published: Oct. 1, 2020

Abstract The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense is overexpressed in multiple human cancers. Recent studies revealed that overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression (SLC7A11 ) also have endure the significant cost associated SLC7A11-mediated metabolic reprogramming, leading glucose- glutamine-dependency cells, which presents potential vulnerabilities therapeutic targeting cancer. In this review, we summarize diverse regulatory mechanisms cancer, discuss ferroptosis-dependent -independent promoting development, explore mechanistic basis SLC7A11-induced nutrient dependency conceptualize strategies target treatment. This review will provide foundation further understanding dependency, biology developing novel effective therapies.

Language: Английский

Citations

1499
KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors DOI Open Access
David S. Hong, Marwan Fakih, John H. Strickler

et al.

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 383(13), P. 1207 - 1217

Published: Sept. 20, 2020

No therapies for targeting

Language: Английский

Citations

1355
Sotorasib for Lung Cancers with KRAS p.G12C Mutation DOI Open Access
Ferdinandos Skoulidis, Bob T. Li, Grace K. Dy

et al.

New England Journal of Medicine, Journal Year: 2021, Volume and Issue: 384(25), P. 2371 - 2381

Published: June 4, 2021

Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors a phase 1 study, and particularly promising was observed subgroup of non–small-cell lung cancer (NSCLC).

Language: Английский

Citations

1248
RAS-targeted therapies: is the undruggable drugged? DOI Open Access
Amanda R. Moore, Scott Rosenberg, Frank McCormick

et al.

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 19(8), P. 533 - 552

Published: June 11, 2020

Language: Английский

Citations

811
The Frequency of Ras Mutations in Cancer DOI Open Access
Ian A. Prior,

Fiona E. Hood,

James L. Hartley

et al.

Cancer Research, Journal Year: 2020, Volume and Issue: 80(14), P. 2969 - 2974

Published: March 24, 2020

Ras is frequently mutated in cancer, however, there a lack of consensus the literature regarding cancer mutation frequency Ras, with quoted values varying from 10%-30%. This variability at least part due to selective aggregation data different databases and dominant influence particular types isoforms within these datasets. To provide more definitive figure for we cross-referenced all major publicly accessible determine reliable each isoform types. These percentages were then applied current U.S. incidence statistics estimate number new patients year that have Ras-mutant cancers. We find approximately 19% harbor mutations, equivalent 3.4 million cases per worldwide. discuss mutation-specific trends evident datasets are relevant Ras-targeted therapies.

Language: Английский

Citations

775
KRAS mutation: from undruggable to druggable in cancer DOI Creative Commons

Lamei Huang,

Zhixing Guo, Fang Wang

et al.

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

Citations

600
Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors DOI Open Access
Brian A. Lanman,

Jennifer R. Allen,

John G. Allen

et al.

Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 63(1), P. 52 - 65

Published: Dec. 10, 2019

KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable yet be identified. Here, we report efforts exploit cryptic pocket (H95/Y96/Q99) identified identify suitable for clinical development. Structure-based design leading identification novel quinazolinone scaffold are described, along with optimization that overcame configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical resulting leads culminated AMG 510, highly potent, selective, and well-tolerated inhibitor currently phase I trials (NCT03600883).

Language: Английский

Citations

536