Current and future perspectives of liquid biopsies in genomics-driven oncology

Nature Reviews Genetics, Journal Year: 2018, Volume and Issue: 20(2), P. 71 - 88

Published: Nov. 8, 2018

Language: Английский

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Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens

Nature, Journal Year: 2019, Volume and Issue: 568(7753), P. 511 - 516

Published: April 10, 2019

Language: Английский

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The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients

Cancer Discovery, Journal Year: 2019, Volume and Issue: 10(1), P. 54 - 71

Published: Oct. 29, 2019

Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, inhibits KRAS-dependent signaling. demonstrated pronounced tumor regression 17 26 (65%) KRASG12C-positive cell line- patient-derived xenograft models from multiple types, objective responses observed patients with lung colon adenocarcinomas. Comprehensive pharmacodynamic pharmacogenomic profiling sensitive partially resistant nonclinical mechanisms implicated limiting antitumor activity including nucleotide cycling pathways induce feedback reactivation and/or bypass dependence. These factors included activation receptor tyrosine kinases (RTK), dependence, genetic dysregulation cycle. Combinations agents RTKs, mTOR, or cycle enhanced response marked several models, MRTX849-refractory models. SIGNIFICANCE: The discovery provides long-awaited opportunity patients. in-depth characterization activity, elucidation resistance mechanisms, identification effective combinations provide new insight toward dependence the rational development this class agents.See related commentary by Klempner Hata, p. 20.This article is highlighted In This Issue feature, 1.

Language: Английский

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Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy

Science, Journal Year: 2017, Volume and Issue: 359(6375), P. 582 - 587

Published: Dec. 7, 2017

HLA genotype affects response Immunotherapy works by activating the patient's own immune system to fight cancer. For effective tumor killing, CD8 + T cells recognize peptides presented human leukocyte antigen class I (HLA-I) molecules. In humans, there are three major HLA-I genes ( HLA-A, HLA-B , and HLA-C ). Chowell et al. asked whether germline influences how respond checkpoint inhibitor immunotherapies (see Perspective Kvistborg Yewdell). They examined more than 1500 patients found that heterozygosity at loci was associated with better survival homozygosity for one or genes. Thus, specific mutations could have implications recognition design of epitopes cancer vaccines immunotherapies. Science this issue p. 582 ; see also 516

Language: Английский

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Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Cancer Cell, Journal Year: 2018, Volume and Issue: 33(5), P. 843 - 852.e4

Published: April 12, 2018

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing examine non-small-cell cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent PD-L1 expression the strongest feature associated efficacy multivariable analysis. The low rate NSCLCs demonstrates immunotherapy does not overcome negative predictive impact TMB. This study association between NSCLC. should be incorporated future trials examining PD-(L)1

Language: Английский

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Pan-cancer whole-genome analyses of metastatic solid tumours

Nature, Journal Year: 2019, Volume and Issue: 575(7781), P. 210 - 216

Published: Oct. 23, 2019

Abstract Metastatic cancer is a major cause of death and associated with poor treatment efficacy. A better understanding the characteristics late-stage required to help adapt personalized treatments, reduce overtreatment improve outcomes. Here we describe largest, our knowledge, pan-cancer study metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs normal tissue, analysed at median depths 106× 38×, respectively, surveying more than 70 million somatic variants. The characteristic mutations lesions varied widely, that reflect those primary types, high rates duplication events (56%). Individual were relatively homogeneous, vast majority (96%) driver being clonal up 80% tumour-suppressor genes inactivated bi-allelically by different mutational mechanisms. Although genomes showed similar landscape tumours, find could contribute responsiveness therapy or resistance in individual patients. We implement an approach review clinically relevant associations their potential actionability. For 62% patients, identify genetic variants may be used stratify patients towards therapies either have been approved are clinical trials. This demonstrates importance comprehensive genomic profiling precision medicine cancer.

Language: Английский

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The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities

Nature Reviews Clinical Oncology, Journal Year: 2020, Volume and Issue: 17(9), P. 527 - 540

Published: May 12, 2020

Language: Английский

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Liquid biopsy enters the clinic — implementation issues and future challenges

Nature Reviews Clinical Oncology, Journal Year: 2021, Volume and Issue: 18(5), P. 297 - 312

Published: Jan. 20, 2021

Language: Английский

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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

Cancer Cell, Journal Year: 2020, Volume and Issue: 39(2), P. 154 - 173

Published: Oct. 30, 2020

Language: Английский

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HER2-targeted therapies — a role beyond breast cancer

Nature Reviews Clinical Oncology, Journal Year: 2019, Volume and Issue: 17(1), P. 33 - 48

Published: Sept. 23, 2019

Language: Английский

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