KRAS ≈ KRAS
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KRAS <sup>G12C</sup> Inhibition with Sotorasib in Advanced Solid Tumors Open
Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen…
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Sotorasib for Lung Cancers with <i>KRAS</i> p.G12C Mutation Open
In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 Clini…
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<i>STK11/LKB1</i> Mutations and PD-1 Inhibitor Resistance in <i>KRAS</i>-Mutant Lung Adenocarcinoma Open
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in…
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Integrated genomic and molecular characterization of cervical cancer Open
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical can…
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Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer Open
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering…
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Molecular Determinants of Response to Anti–Programmed Cell Death (PD)-1 and Anti–Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non–Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing Open
Purpose Treatment of advanced non–small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and u…
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Colon Cancer, Version 1.2017, NCCN Clinical Practice Guidelines in Oncology Open
This portion of the NCCN Guidelines for Colon Cancer focuses on the use of systemic therapy in metastatic disease. Considerations for treatment selection among 32 different monotherapies and combination regimens in up to 7 lines of therapy…
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T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer Open
We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the i…
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The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients Open
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 cy…
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Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers Open
This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.
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VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research Open
Accurate variant calling in next generation sequencing (NGS) is critical to understand cancer genomes better. Here we present VarDict, a novel and versatile variant caller for both DNA- and RNA-sequencing data. VarDict simultaneously calls…
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RAS isoforms and mutations in cancer at a glance Open
RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP–GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS gen…
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Adagrasib in Non–Small-Cell Lung Cancer Harboring a <i> KRAS <sup>G12C</sup> </i> Mutation Open
In patients with previously treated KRASG12C -mutated NSCLC, adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati Therapeutics; ClinicalTrials.gov number, NCT03785249.).
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Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With <i>KRAS</i> Wild-Type Advanced or Metastatic Colorectal Cancer Open
clinicaltrials.gov identifier: NCT00265850.
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KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer Open
RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. With the highest RAS mutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pa…
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Generation and testing of clinical-grade exosomes for pancreatic cancer Open
Exosomes are extracellular vesicles produced by all cells with a remarkable ability to efficiently transfer genetic material, including exogenously loaded siRNA, to cancer cells. Here, we report on a bioreactor-based, large-scale productio…
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Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State Open
KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we…
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<i>MET</i> Exon 14 Mutations in Non–Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent <i>MET</i> Genomic Amplification and c-Met Overexpression Open
Purpose Non–small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer w…
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Assessment of Resistance Mechanisms and Clinical Implications in Patients With<i>EGFR</i>T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib Open
Acquired resistance to osimertinib mediated by loss of the T790M mutation is associated with early resistance and a range of competing resistance mechanisms. These data provide clinical evidence of the heterogeneity of resistance in advanc…
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Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism Open
Cancer therapy by entrapment Mutations in the KRAS oncogene occur at high frequency in several of the most lethal human cancers, including lung and pancreatic cancer. Substantial effort has thus been directed toward developing KRAS inhibit…
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Discovery of a Covalent Inhibitor of KRAS<sup>G12C</sup> (AMG 510) for the Treatment of Solid Tumors Open
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable inh…
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Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients Open
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation …
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Lung adenocarcinoma promotion by air pollutants Open
A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in heal…
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Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS <sup>G12D</sup> Inhibitor Open
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inh…
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The role of TGF-β/SMAD4 signaling in cancer Open
Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as t…
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Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease Open
Rosai-Dorfman-Destombes disease (RDD) is a rare non–Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis class…
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Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein Open
KRAS is the most frequently mutated oncogene in human neoplasia. Despite a large investment to understand the effects of KRAS mutation in cancer cells, the direct effects of the oncogenetic KRAS activation on immune cells remain elusive. H…
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Tissue of origin dictates branched-chain amino acid metabolism in mutant<i>Kras</i>-driven cancers Open
Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific meta…
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Combined BRAF, EGFR, and MEK Inhibition in Patients with <i>BRAF</i> V600E-Mutant Colorectal Cancer Open
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colo…
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Identification of the Clinical Development Candidate <b>MRTX849</b>, a Covalent KRAS<sup>G12C</sup> Inhibitor for the Treatment of Cancer Open
Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously repo…