A5057777319- Lung Cancer Treatments and Mutations
- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- CRISPR and Genetic Engineering
- Cancer, Lipids, and Metabolism
- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Protein Kinase Regulation and GTPase Signaling
- Prostate Cancer Treatment and Research
- Microtubule and mitosis dynamics
- Cytokine Signaling Pathways and Interactions
- Cancer therapeutics and mechanisms
- Pluripotent Stem Cells Research
- RNA modifications and cancer
- Virus-based gene therapy research
- Metabolomics and Mass Spectrometry Studies
- Cellular Mechanics and Interactions
- Cancer Mechanisms and Therapy
- Pancreatic and Hepatic Oncology Research
- Gastric Cancer Management and Outcomes
- Phagocytosis and Immune Regulation
- Cancer Genomics and Diagnostics
- Protein Tyrosine Phosphatases
- RNA Research and Splicing
- Metabolism, Diabetes, and Cancer
Harvard University
2002-2023
Massachusetts General Hospital
2000-2023
Cold Spring Harbor Laboratory
2008-2021
Stony Brook University
2016-2017
ORCID
2017
Cornell University
2013-2014
Cancer Center at Cold Spring Harbor Laboratory
2014
Metabolon (United States)
2013
Dana-Farber/Harvard Cancer Center
2005
Most patients with non–small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets epidermal growth factor receptor (EGFR). However, about 10 percent of a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity gefitinib are unknown.
Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within EGFR domain. We report these mutant EGFRs selectively activate Akt signal transduction activator of transcription (STAT) signaling pathways, which promote survival, but have no effect on extracellular signal–regulated signaling, proliferation....
Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to reversible tyrosine inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation EGFR domain, T790M, conferring drug resistance, other cases mechanism underlying acquired resistance is unknown. In studying multiple sites NSCLCs, we detected T790M only small percentage...
Protein interaction mapping using large-scale two-hybrid analysis has been proposed as a way to functionally annotate large numbers of uncharacterized proteins predicted by complete genome sequences. This approach was examined in Caenorhabditis elegans , starting with 27 involved vulval development. The resulting map reveals both known and new potential interactions provides functional annotation for approximately 100 gene products. A protein project is now feasible C. on genome-wide scale...
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...
The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. majority patients, however, will eventually develop resistance and succumb disease. Recent studies have identified secondary mutations (EGFR T790M) amplification N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms acquired...
Kinase inhibitors constitute an important new class of cancer drugs, whose selective efficacy is largely determined by underlying tumor cell genetics. We established a high-throughput platform to profile 500 lines derived from diverse epithelial cancers for sensitivity 14 kinase inhibitors. Most were ineffective against unselected but exhibited dramatic killing small nonoverlapping subsets. Cells with exquisite EGFR, HER2, MET, or BRAF marked activating mutations amplification the drug...
Abstract Somatic mutations within the epidermal growth factor receptor (EGFR) kinase domain are detected in 10% to 30% of human non–small cell lung cancers and correlated with striking clinical responses a subset patients treated EGFR inhibitors, such as gefitinib erlotinib. Cell-based studies suggest that these mutant EGFRs promote increased autophosphorylating activity on COOH-terminal tyrosines consequent engagement downstream effectors. Because function is regulated at multiple levels...
Deletions on chromosome 8p are common in human tumors, suggesting that one or more tumor suppressor genes reside this region. Deleted Liver Cancer 1 ( DLC1 ) encodes a Rho-GTPase activating protein and is candidate suppressor. We show knockdown cooperates with Myc to promote hepatocellular carcinoma mice, reintroduction of wild-type into hepatoma cells low levels suppresses growth situ. Cells reduced contain increased GTP-bound RhoA, enforced expression constitutively activated RhoA allele...
Abstract The CRISPR/Cas9 system is a powerful tool for studying gene function. Here, we describe method that allows temporal control of activity based on conditional Cas9 destabilization. We demonstrate fusing an FKBP12-derived destabilizing domain to (DD-Cas9) enables expression and editing in the presence FKBP12 synthetic ligand. This can be easily adapted co-express, from same promoter, DD-Cas9 with any other interest without co-modulation latter. In particular, when co-expressed...
Significance p53 is one of the most intensively studied tumor-suppressor genes. We identified a naturally occurring isoform, generated by an alternative-splicing event, that, although lacking transcriptional activity and canonical tumor suppressor functions, able to reprogram cells toward acquisition metastatic features via cyclophilin D interaction in mitochondria matrix. Interestingly, this isoform expressed on tissue injury tumors characterized increased spread. In some these tumors,...
Cancer cells undergo a metabolic reprogramming but little is known about alterations of other within tumors. We use mass spectrometry-based profiling and pathway-based systems analysis to compare 21 primary human lung cancer-associated fibroblast lines (CAF) "normal" (NF) generated from adjacent nonneoplastic tissue. CAFs are protumorigenic, although the mechanisms by which support tumors have not been elucidated. identified several pathways whose metabolite abundance globally distinguished...
TP53 truncating mutations are common in human tumors and thought to give rise p53-null alleles. Here, we show that exon-6 occur at higher than expected frequencies produce proteins lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, metastasis. Functionally molecularly, these mutants resemble the naturally occurring alternative splice variant, p53-psi. Accordingly, can localize mitochondria where they phenotypes by binding activating inner pore...
We have recently recapitulated metastasis of human PTEN/TP53-mutant prostate cancer in the mouse using RapidCaP system. Surprisingly, we found that this is driven by MYC, and not AKT, activation. Here, show cell-cell communication IL6 drives AKT-MYC switch through activation AKT-suppressing phosphatase PHLPP2, when PTEN p53 are lost together, but separately. then communicates a downstream program STAT3-mediated MYC activation, which cell proliferation. Similarly, tissues, peak proliferation...
Myogenesis is an intricate process that coordinately engages multiple intracellular signaling cascades. The Rho family GTPase RhoA known to promote myogenesis, however, the mechanisms controlling its regulation in myoblasts have yet be fully elucidated. We show here SH2-containing protein tyrosine phosphatase, SHP-2, functions as early modulator of myogenesis by regulating RhoA. When MyoD was expressed fibroblasts lacking functional muscle-specific gene activity impaired and abolition SHP-2...
Plexins are transmembrane receptors for semaphorins, guiding cell migration and axon extension. Plexin activation leads to the disassembly of integrin-based focal adhesive structures actin cytoskeleton remodelling inhibition migration; however, underlying molecular mechanisms unclear. We consistently observe a transient decrease cellular RhoA-GTP levels upon plexin in adherent cells. One main effectors RhoA downregulation is p190, ubiquitously expressed GTPase activating protein (GAP). show...
Abstract Purpose: Somatic mutations in the epidermal growth factor receptor (EGFR) gene occur a subset of non–small-cell lung cancer (NSCLC) and are highly predictive clinical response to selective EGFR kinase inhibitors. The prevalence EGFR-mutant NSCLC is appreciably higher females than males East Asian Caucasian populations. We hypothesized that these disparate frequencies may be attributable underlying genetic modifiers. Given coincident differences sex ethnic origin, we tested...
A core evolutionary function of the p53 family is to protect genomic integrity gametes. However, role p73 in male germ line unknown. Here, we reveal that TAp73 unexpectedly functions as an adhesion and maturation factor seminiferous epithelium orchestrating spermiogenesis. knockout (TAp73KO) p73KO mice, but not ΔNp73KO display a "near-empty tubule" phenotype due massive premature loss immature cells. The cellular basis this defective cell-cell adhesions developing cells Sertoli nurse cells,...