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Udayan Guha, M.D., Ph.D.

Portait Photo of Udayan Guha
Thoracic and Gastrointestinal Oncology Branch
Head, Cancer Signaling Networks Section
Center for Cancer Research
National Cancer Institute
Building 10, Room 13N240-C
Bethesda, MD 20892
Fax Number not listed


Dr. Guha earned his M.B.B.S. from the All India Institute of Medical Sciences in New Delhi, India. He then received his Ph.D. in neuroscience at the Albert Einstein College of Medicine in New York. During his graduate studies, Dr. Guha developed tissue-specific transgenic mice to study bone morphogenetic protein (BMP) signaling in neuronal, hair follicle, and limb development. He then received training in internal medicine at the Jacobi Medical Center and was subsequently awarded an oncology fellowship to Memorial Sloan-Kettering Cancer Center (MSKCC), New York. Dr. Guha performed his postdoctoral training in the laboratory of Dr. Harold Varmus at MSKCC. He studied mutant epidermal growth factor receptor (EGFR) signaling in lung cancer, employing quantitative proteomics and mouse modeling. Dr. Guha is board certified in internal medicine and oncology.


Our research aims to clarify the perturbed-signaling pathways that cause tumorigenesis. This work promises to enhance, and builds upon, the various powerful strategies that are currently used to study genomic changes in different tumor types. These approaches have identified hundreds of somatic genetic changes that occur during tumorigenesis (e.g., mutations, gene rearrangement, and copy-number alteration). Only a small subset of these changes is expected to consist of 'driver' mutations (i.e., those mutations that confer a selective advantage on the tumor cells and so may be needed for tumorigenesis). The other changes are considered 'passengers' (i.e., not needed for tumorigenesis). Recently, an integrative analysis of genetic and epigenetic changes as well as expression-array data has been initiated under the auspices of The Cancer Genome Atlas (TCGA) project (Cancer Genome Atlas Research Network, 2008). It is well known that the consequences of these genetic changes are manifested in altered protein expression, post-translational modification, and hence perturbed signaling pathways. Global analysis of these changes at the protein level is expected to supplement the above-referenced large-scale studies and thus notably increase our understanding of tumor biology. Our research will contribute to reaching this goal.

Additionally, our work has direct therapeutic implications. Current available targeted therapy is generally directed towards mutant kinases that have proved to be 'druggable' targets. Our research will enhance our understanding of global post-translational modification changes (e.g., in Tyr or Ser/Thr phosphorylation of proteins in tumor cells). This knowledge will not only help unravel the key mechanisms of tumorigenesis by the mutant oncogenes or tumor suppressors, it will also help identify additional potential targets for treatment.

Tyr and Ser/Thr Phosphorylation of Downstream Targets of Lung Cancer-specific Mutant EGFRs

The main focus of our research centers on the
the limitations of existing lung cancer treatment methodologies. Targeted therapy with an epidermal growth factor receptor (EGFR)-selective tyrosine kinase inhibitor (TKI) has generated significant hope among researchers as a lung cancer treatment. Mutations in the EGFR gene have been associated with sensitivity of lung cancer patients to tyrosine kinase inhibitors (TKIs) such as gefitinib (Iressa) or erlotinib (TarcevaTM). However, only about 10% of patients in the U.S. who harbor the EGFR mutation respond to these targeted agents. Moreover, even those patients who initially respond will invariably develop secondary resistance to the TKIs during the course of their treatment. The overall goal of our research efforts is to identify direct or indirect targets of mutant EGFR signaling in lung cancer.

We have therefore undertaken a quantitative mass spectrometry-based unbiased approach to this problem. We are using isogenic human bronchial epithelial cells (HBECs), as well as human lung adenocarcinoma cell lines with differential sensitivities to TKIs, as model systems to interrogate EGFR signaling. We utilize stable isotope labeling with amino acids in cell culture (SILAC), enrichment approaches using immune-affinity purification, strong cation exchange (SCX) fractionation, and TiO2-mediated enrichment, followed by liquid chromatography and tandem mass spectrometry to identify phosphorylated peptides and quantify the degree of phosphorylation at specific sites in these proteins. Likewise, we also follow the dynamics of phosphorylation changes in lung adenocarcinoma cell lines after growth factor stimulation and TKI inhibition. These approaches have the potential to identify mechanisms of TKI resistance, biomarkers of TKI response, and potential targets for treatment.

Additionally, we have undertaken a variety of approaches to validate candidates identified by our mass spectrometry-based screens. These include siRNA or shRNA-mediated knockdown strategies; site-directed mutagenesis of phosphorylation sites; mouse modeling of lung tumorigenesis; and validation of phosphorylation in human lung cancer patient samples, using tissue microarrays (TMAs) and luminex assays.

Mouse Models of Lung Tumorigenesis

We use a doxycycline-inducible mutant EGFR transgenic mouse (Politi et al., Genes Dev. 2006) as a model of lung tumorigenesis. One of the targets identified in our proteomics-based screens is mitogen-inducible gene 6 (Mig-6, gene symbol ERRFI1). We have shown that mutant EGFR cooperates with a loss of ERRFI1 expression to promote lung tumorigenesis in vivo. Further studies are underway to interrogate the whole subject of tumor regression attendant on either doxycycline withdrawal or TKI administration. We use MRI imaging to assess the treatment response. The lung tumor generated in this model is used in both genomics and proteomics studies as a complementary approach to our cell line-based studies.

This page was last updated on 4/10/2014.