A5067248479- Lung Cancer Treatments and Mutations
- RNA modifications and cancer
- Cancer Immunotherapy and Biomarkers
- Cancer Genomics and Diagnostics
- Lung Cancer Research Studies
- HER2/EGFR in Cancer Research
- Cancer, Hypoxia, and Metabolism
- Colorectal Cancer Treatments and Studies
- PI3K/AKT/mTOR signaling in cancer
- Cytokine Signaling Pathways and Interactions
- Immunotherapy and Immune Responses
- Radiopharmaceutical Chemistry and Applications
- Microwave-Assisted Synthesis and Applications
- Cancer therapeutics and mechanisms
- Synthesis and biological activity
- Cancer Cells and Metastasis
- Gastric Cancer Management and Outcomes
- Immune Cell Function and Interaction
- Cancer Mechanisms and Therapy
- Lung Cancer Diagnosis and Treatment
- Ferroptosis and cancer prognosis
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Quinazolinone synthesis and applications
- Immune cells in cancer
Yale University
2016-2025
Yale Cancer Center
2015-2024
University of New Haven
2011-2024
University Medical Center
2017
Memorial Sloan Kettering Cancer Center
2006-2015
Cancer Genetics (United States)
2006-2014
Institute of Cancer Research
2014
Cancer Research UK
2012-2014
National Human Genome Research Institute
2012-2014
The Netherlands Cancer Institute
2014
Somatic mutations in the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity lung cancers to gefitinib (Iressa), inhibitor. In-frame deletions occur exon 19, whereas point frequently codon 858 (exon 21). We found from sequencing EGFR TK that 7 10 gefitinib-sensitive tumors had similar types alterations; no were eight gefitinib-refractory ( P = 0.004). Five seven sensitive erlotinib (Tarceva), a related inhibitor for which...
Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding domain of epidermal growth factor receptor (EGFR). Despite initial responses, eventually progress by unknown mechanisms "acquired" resistance.We show that two five with acquired resistance erlotinib, progressing tumors contain, addition a primary drug-sensitive mutation EGFR, secondary exon 20, which...
Abstract EGF receptor (EGFR)–mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models human patients. Because is also a potent HER2 inhibitor, we investigated the role EGFR-mutant tumor cells. We show vitro vivo that plus significantly inhibits phosphorylation. overexpression or knockdown confers sensitivity, respectively, all...
Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection 14 ICI-resistant lung cancer samples investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play role PD-1 PD-L1 antagonistic antibodies. Recurrent mutations copy-number changes were not detected our cohort. In one case, we found homozygous loss B2M that caused lack cell-surface...
Somatic mutations in exons encoding the tyrosine kinase domain of epidermal growth factor receptor ( EGFR ) gene are found human lung adenocarcinomas and associated with sensitivity to inhibitors gefitinib erlotinib. Nearly 90% either short, in-frame deletions exon 19 or point that result substitution arginine for leucine at amino acid 858 (L858R). To study further role these initiation maintenance cancer, we have developed transgenic mice express an deletion mutant Δ L747–S752 L858R type II...
Purpose: Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses uniquely challenging interpret because tumors often shrink slowly can appear transiently enlarged due inflammation. We hypothesized that monitoring cell death in real time quantifying changes circulating DNA (ctDNA) levels could enable early assessment of efficacy.Experimental Design: compared longitudinal ctDNA...
EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses individuals with lung adenocarcinomas characterized by mutations exons encoding domain, but disease progression invariably occurs. A reason for acquired resistance outgrowth tumor cells additional TKI-resistant mutations. Here we used relevant transgenic mouse models to evaluate...
Background Mutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung cancers to kinase inhibitors like erlotinib. Mechanisms cell death that occur after inhibition these oncogene-dependent tumors have not been well delineated. We sought improve understanding this process order provide insight into mechanisms and/or resistance tyrosine and uncover new targets for therapy. Methods Findings Using a panel human cancer lines harbor EGFR...
BackgroundAlthough EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some do respond these therapies; however, there is a lack of understanding the characteristics lung responsive blockade.Patients and methodsWe retrospectively analyzed de-identified clinical molecular data on 171 cases treated with inhibitors from Yale Cancer Center, Memorial Sloan Kettering University California Los Angeles, Dana Farber Institute. A separate cohort 383 cancer sequencing...
Abstract Purpose: To determine the tumor tissue/cell distribution, functional associations, and clinical significance of PD-1, LAG-3, TIM-3 protein expression in human non–small cell lung cancer (NSCLC). Experimental Design: Using multiplexed quantitative immunofluorescence, we performed localized measurements CD3, >800 clinically annotated NSCLCs from three independent cohorts represented tissue microarrays. Associations between marker's major genomic alterations were studied The...
Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due a second mutation, most commonly T790M. Through genome-wide siRNA screen human lung cancer cell line analyses of murine mutant EGFR-driven adenocarcinomas, we found that was reduced expression neurofibromin, RAS GTPase-activating protein encoded by NF1 gene. Erlotinib failed...
Abstract Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) a multi-institutional effort to identify and treat oncogenic driver events in Experimental Design: Sixteen U.S. institutions enrolled 1,367 cancer LCMC2; 904 were deemed eligible had at least one 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, IHC. Results: use targeted...
Significance Knowledge of oncogenic alterations that drive lung adenocarcinoma formation has enabled the development genetically engineered mouse models are increasingly being used to study biology and therapeutic vulnerabilities this disease. Given importance genomic in these processes human cancer, information on mutational landscape tumors is valuable for design interpretation experiments. In study, we compared whole-exome sequencing data from adenocarcinomas induced by different...
The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role intratumoral T-cells their association with tumor genomic landscape, we perform paired whole exome DNA sequencing multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated PD-1 axis blockers. QIF is used simultaneously measure level CD3+ infiltrating lymphocytes (TILs), situ...
Abstract Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, role of FA LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate FASN, rate-limiting enzyme synthesis, while being dispensable EGFR-mutant or wild-type LC, required for viability cells. Integrating lipidomic, transcriptomic functional analyses,...
Treatment with anti–PD-1 and anti-PD-L1 therapies has shown durable clinical benefit in non–small cell lung cancer (NSCLC). However, patients NSCLC epidermal growth factor receptor (EGFR) mutations do not respond as well to treatment without an EGFR mutation. We show that EGFR-mutated expressed higher levels of CD73 compared WT tumors expression was regulated by signaling. lines were significantly more resistant T killing through suppression proliferation function. In a xenograft mouse model...
Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility gene regulatory signatures of sensitive resistant cell patient-derived models uncover a role for mammalian SWI/SNF remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, identify both shared cancer line-specific targets...
In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of mutant oncoprotein. Therapeutic inhibition these oncoproteins can massive apoptosis tumor cells, leading to sometimes dramatic regressions in patients. The PI3K and MAPK signaling pathways are central regulators oncogenic transformation maintenance. We hypothesized that upstream engages either one preferentially "downstream" dependency. Therefore, we analyzed whether downstream pathway...
To explore the potential involvement of aberrant Notch1 signaling in breast cancer pathogenesis, we have used a transgenic mouse model. In these animals, mammary tumor virus LTR-driven expression constitutively active intracellular domain receptor (N1(IC)) causes development lactation-dependent tumors that regress upon gland involution but progress to nonregressing, invasive adenocarcinomas subsequent pregnancies. Up-regulation Myc prompted genetic investigation Notch1/Myc functional...
Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase β cell mass and impaired glucose-dependent release. proliferation are thought to be regulated by signaling through receptor tyrosine kinases. In this regard, we sought examine the potential proliferative and/or antiapoptotic role IGFs in cells tissue-specific conditional mutagenesis ablating 1 IGF (IGF1R) signaling. Unexpectedly, lack functional IGF1R did not affect mass, but...