A5003183589- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Fibroblast Growth Factor Research
- Cancer therapeutics and mechanisms
- Cytokine Signaling Pathways and Interactions
- RNA modifications and cancer
- Medical Imaging and Pathology Studies
- Eosinophilic Disorders and Syndromes
- Cancer, Hypoxia, and Metabolism
- Lung Cancer Research Studies
- Colorectal Cancer Treatments and Studies
- Melanoma and MAPK Pathways
- Monoclonal and Polyclonal Antibodies Research
- Radiopharmaceutical Chemistry and Applications
- Cancer Mechanisms and Therapy
- Radiomics and Machine Learning in Medical Imaging
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Lipids, and Metabolism
- Synthesis and Reactions of Organic Compounds
- Quinazolinone synthesis and applications
- Cancer Genomics and Diagnostics
- Kruppel-like factors research
- Protein Tyrosine Phosphatases
- Metastasis and carcinoma case studies
- Congenital Diaphragmatic Hernia Studies
Moffitt Cancer Center
2023-2025
Dana-Farber Cancer Institute
2009-2021
Harvard University
2012-2017
Northeastern University
2016
Center for Neuro-Oncology
2015
Center for Orthopaedics
2009-2014
Brigham and Women's Hospital
2011-2013
Dana-Farber/Harvard Cancer Center
2012-2013
Howard Hughes Medical Institute
2013
Harvard University Press
2013
Cetuximab, an antibody directed against the epidermal growth factor receptor, is effective clinical therapy for patients with colorectal, head and neck, non-small cell lung cancer, particularly those KRAS BRAF wild-type cancers. Treatment in all limited eventually by development of acquired resistance, but little known about underlying mechanism. Here, we show that activation ERBB2 signaling lines, either through amplification or heregulin up-regulation, leads to persistent extracellular...
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...
Abstract Purpose: Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models lung cancer patients harboring the T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired to this class of inhibitors. We sought identify study mutations that confer agents. Experimental Design: performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen EGFR-mutant (sensitizing...
Abstract The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development drug resistance. irreversible EGFR inhibitor WZ4002 effective against most common mechanism resistance mediated T790M mutation. Here, we show, in multiple complementary models, that to develops through aberrant activation extracellular signal-regulated (ERK) signaling caused either an amplification mitogen-activated protein 1 (MAPK1) or downregulation negative regulators...
Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and inhibitor-resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective inhibitors is effective clinically in lung cancer patients harboring EGFR(T790M), prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations activate ERK1/2 signaling. Here, we find reactivation occurs rapidly following WZ4002...
Abstract mTOR is a highly conserved serine/threonine protein kinase that serves as central regulator of cell growth, survival, and autophagy. Deregulation the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer numerous inhibitors targeting ATP-binding site these kinases are currently undergoing clinical evaluation. Here, we report characterization Torin2, second-generation ATP-competitive inhibitor potent selective for with superior pharmacokinetic profile to previous inhibitors....
The clinical efficacy of EGF receptor (EGFR) kinase inhibitors gefitinib and erlotinib is limited by the development drug resistance. most common mechanism resistance secondary EGFR T790M mutation. Strategies to overcome T790M-mediated include use mutant selective inhibitors, including WZ4002, or high concentrations irreversible quinazoline such as PF299804. In current study, we develop drug-resistant versions EGFR-mutant PC9 cell line, which reproducibly develops a gefitinib. Neither...
Significance Inhibitors of the FGF receptors (FGFRs) are currently under clinical investigation for treatment various cancers. All approved kinase inhibitors eventually rendered useless by emergence drug-resistant tumors. We used structure-based drug design to develop first, our knowledge, selective, next-generation covalent FGFR that can overcome most common form inhibitor resistance, mutation so-called “gatekeeper” residue located in ATP-binding pocket. also describe a novel strategy uses...
Insertion mutations in EGFR and HER2 both occur at analogous positions exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these seldom achieve clinical responses to dacomitinib afatinib, two covalent quinazoline-based inhibitors of or HER2, respectively. In this study, we investigated the effects specific 20 insertion from NSCLC that had clinically achieved a partial response after treatment. We identified Gly770 as common feature among drug-sensitive mutations....
Tyrosine kinase inhibitors (TKI) that target the EGF receptor (EGFR) are effective in most non-small cell lung carcinoma (NSCLC) patients whose tumors harbor activating EGFR domain mutations. Unfortunately, acquired resistance eventually emerges these chronically treated cancers. Two of common mechanisms to TKIs seen clinically acquisition a secondary "gatekeeper" T790M mutation increases affinity mutant for ATP and activation MET offset loss signaling. Although up one-third patient...
Targetable oncogenic alterations are detected more commonly in patients with non-small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known do not account for all smokers develop NSCLC. We sought to identify additional from NSCLC define treatment options.We analyzed 576 adenocarcinomas of Asian and Caucasian ethnicity. identified a subset cancers that did harbor any...
Efforts to discover drugs that overcome resistance targeted therapies in patients with rare oncogenic alterations, such as NTRK1 and ROS1 rearrangements, are complicated by the cost protracted timeline of drug discovery.
MET targeted therapies are under clinical evaluation for non‐small‐cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKI) against have varying degrees of specificity. Tivantinib (ARQ 197) is reported to be a non‐ATP competitive selective inhibitor. We aimed compare the activity tivantinib established TKIs in panel NSCLC cell lines characterized by their dependency and different relevant genotypes. A549, H3122, PC9 HCC827, respective resistant clones GR4 HCC827 GR6 amplified...
Abstract Purpose: Sarcopenia is a hallmark of cancer cachexia. Chimeric antigen receptor (CAR) T-cell therapy associated with an inflammatory state that may exacerbate sarcopenia. The relationship between CAR therapy, sarcopenia, and metabolism poorly understood. Experimental Design: In 83 large B-cell lymphoma patients, the skeletal muscle index (SMI) was measured from clinical images obtained at baseline days 30 90 post-therapy. Serum metabolomics (n=57 patients) performed in first 4...
Abstract Background: KRAS mutations occur in ∼25% of lung adenocarcinomas (LUAD), with KRASG12C being the most common. There has been limited clinical success inhibitors due intrinsic/acquired resistance. EMT is a known mechanism by which cancer cells become resistant to targeted therapy. Here, we aim map protein interactors using proximity-dependent biotin labeling (BioID) gain insights into key regulators/effectors oncogenic signaling and therapy Methods: Dox-inducible fusion BirA ligase...
The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets lung cancer patients. identification additional drug-sensitive alterations may similarly lead new therapeutic approaches cancer. We identify characterize novel FGFR2 extracellular domain insertion demonstrate that they are both sensitive inhibition by FGFR kinase inhibitors. mechanism activation transformation is mediated ligand-independent dimerization...