A5074923974- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Colorectal Cancer Treatments and Studies
- Liver physiology and pathology
- Cancer Mechanisms and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related gene regulation
- Cancer, Hypoxia, and Metabolism
- Cytokine Signaling Pathways and Interactions
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Lung Cancer Research Studies
- Protein Kinase Regulation and GTPase Signaling
- Pancreatic and Hepatic Oncology Research
- Biochemical and Molecular Research
- Cancer therapeutics and mechanisms
- Cancer Research and Treatments
- Neuroblastoma Research and Treatments
- Microtubule and mitosis dynamics
- Hippo pathway signaling and YAP/TAZ
- Cancer Cells and Metastasis
- Chemical Reactions and Isotopes
- Melanoma and MAPK Pathways
- Chronic Lymphocytic Leukemia Research
- Cancer Treatment and Pharmacology
Mirati Therapeutics (United States)
2016-2025
Bristol-Myers Squibb (United States)
2024
Pfizer (United States)
2010-2023
RIKEN BioResource Research Center
2023
Centre for Cancer Biology
2009-2023
Memorial Sloan Kettering Cancer Center
2010-2022
Weatherford College
2022
Howard Hughes Medical Institute
2022
Northwestern University
2018
University of Chicago
2018
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive cancer cell line that developed resistance to as result of focal amplification the MET proto-oncogene. inhibition signaling in cells restored their sensitivity gefitinib. was detected 4 18 (22%) specimens had or erlotinib. We find causes by...
Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup non-small-cell lung cancers, representing 2 to 7% such tumors. We explored the therapeutic efficacy inhibiting ALK tumors an early-phase clinical trial crizotinib (PF-02341066), orally available small-molecule inhibitor tyrosine kinase.After screening tumor samples from approximately 1500 patients with cancer for presence rearrangements, we identified 82 advanced ALK-positive disease who...
Lung cancers undergo dynamic genetic and histological changes upon developing resistance to EGFR inhibitors.
Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic inhibition. Crizotinib is small-molecule inhibitor anaplastic lymphoma (ALK), ROS1, and another kinase, MET.
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...
Because of the critical roles aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure 3 (PHA-665752), bound to kinase domain, revealed a novel ATP site environment, which served as target guide parallel, multiattribute drug design. A 2-amino-5-aryl-3-benzyloxypyridine series was created more effectively make key interactions achieved with 3. In series, 2-aminopyridine core allowed...
Inflammatory myofibroblastic tumor (IMT) is a distinctive mesenchymal neoplasm characterized by spindle-cell proliferation with an inflammatory infiltrate. Approximately half of IMTs carry rearrangements the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression. We report sustained partial response to inhibitor crizotinib (PF-02341066, Pfizer) in patient ALK-translocated IMT, as compared no observed activity another without translocation. These results...
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor catalytic activity kinase. selective for (and anaplastic lymphoma kinase) compared with panel >120 diverse serine-threonine kinases. potently inhibited phosphorylation c-Met-dependent proliferation, migration,...
A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma (NPM-ALK) has been implicated the pathogenesis anaplastic large-cell (ALCL). PF-2341066 was recently identified a p.o. bioavailable, small-molecule inhibitor catalytic activity c-Met and NPM-ALK protein. also potently inhibited phosphorylation Karpas299 or SU-DHL-1 ALCL cells (mean IC(50) value, 24 nmol/L). In biochemical cellular screens, shown to be...
Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought describe the clinical, pathologic, genomic characteristics of patients with cancer mutations.We interrogated next-generation sequencing results from 6,376 identify those mutations. Clinical mutated NSCLCs were compared activating KRAS EGFR. Co-occurring copy number alterations identified. immunohistochemistry real-time polymerase chain reaction detect...
Anaplastic lymphoma kinase (ALK) tyrosine inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms ALK TKI resistance identified from a crizotinib-treated non-small cell lung (NSCLC) patient line generated resistant tumor (DFCI076) as well studying version (TAE684)-sensitive H3122...
Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity had an acceptable adverse-event profile the phase 1–1b part of KRYSTAL-1 1–2 study.
Abstract Non–small cell lung cancer (NSCLC) is a difficult disease to treat. The c-Met receptor an attractive potential target for novel therapeutic inhibition in human cancers. We provide strong evidence that overexpressed, activated, and sometimes mutated NSCLC lines tumor tissues. Expression of was found all (100%) the tissues examined (n = 23) most (89%) 9). Sixty-one percent strongly expressed total c-Met, especially adenocarcinoma (67%). Specific expression phospho-Met (p-Met) [Y1003]...
The success of molecular targeted therapy in cancer may depend on the selection appropriate tumor types whose survival depends drug target, so-called “oncogene addiction.” Preclinical approaches to defining drug-responsive subsets are needed if initial clinical trials be directed at most susceptible patient population. Here, we show that gastric cells with high-level stable chromosomal amplification growth factor receptor MET extraordinarily selective inhibitor PHA-665752. Although...
Capping off an era marred by drug development failures and punctuated waning interest presumed intractability toward direct targeting of KRAS, new technologies strategies are aiding in the target's resurgence. As previously reported, tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors KRASG12C that bind switch-II pocket KRAS make a bond to cysteine 12. Using structure-based design conjunction with focused vitro absorption, distribution, metabolism excretion...
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for treatment of solid tumors. However, when compared to KRASG12C, selective inhibition KRASG12D presents significant challenge due requirement inhibitors bind with high enough affinity obviate need covalent interactions mutant protein. Here, we report discovery and characterization first noncovalent, potent, inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement shown be...
Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring glycine-to-cysteine amino acid substitutions at codon 12 (KRAS
Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined GEC cohort with follow-up and reported clinical response four additional patients MET-amplified tumors to small molecule inhibitor crizotinib as part an expanded phase I study.
Abstract Selective kinase inhibitors have had a substantial impact on the field of medical oncology. Whereas these agents can elicit dramatic clinical responses in some settings, their activity is generally limited to subset treated patients whose tumor cells harbor specific genetic lesion. We established an automated platform for examining sensitivity various molecularly targeted across large panel human tumor-derived cell lines identify additional genotype-correlated that may be clinically...