Over-expression of epidermal growth factor receptor (EGFR) drives several cancers including lung, head &neck (H&N) and colorectal, where targeting EGFR kinase activity has produced definite but limited successes. Based on previous reports and our preliminary studies, we hypothesize that the effectiveness of an anti-EGFR therapy can be greatly increased by facilitating EGFR protein degradation as opposed to simple inhibition of its kinase activity. Towards this goal, we have identified a novel interaction between EGFR and a HECT type ubiquitin ligase, Smad ubiquitination regulatory factor 2 (SMURF2), which is critical for EGFR protein stability and by targeting SMURF2 we can efficiently degrade EGFR to kill EGFR addicted cancer cells and stop the growth of human tumor xenografts. We have also discovered significant correlation of expression of the two proteins at the RNA and protein levels in a large group of lung and H&N cancer patients. The main goal of this proposal is to understand the molecular interaction between EGFR and SMURF2 in upper aerodigestive cancers and to develop a novel therapeutic strategy by inducing EGFR degradation via targeting SMURF2. We believe that by down-regulating SMURF2, EGFR will be more vulnerable to degradation, independent of its overexpression or mutation status in cancer and such a strategy will be therapeutically more potent as it can physically abolish EGFR. We propose to achieve these goals through 3 specific aims:
In aim 1, we hypothesize that certain lysine residues are critical for SMURF2 mediated protein ubiquitination, responsible for EGFR protein stability.
Specific aim 1 is to determine whether SMURF2-mediated ubiquitination can covalently modify certain lysine residues on EGFR to stabilize it from undergoing degradation.
In specific aim 2, we hypothesize that by down-regulating SMURF2 via shRNA, we can reduce the tumor burden as individual therapy or can sensitize tumor cells that are resistant to currently available chemo-/radiotherapy.
Specific aim 2 is to explore the therapeutic potential of SMURF2 targeting as a novel approach in upper aerodigestive cancer treatment.
In aim 3, we hypothesize that EGFR and SMURF2 interacts in sequence specific manner in association with certain cofactors.
Specific aim 3 we will identify the domain(s) of EGFR and cofactors that are assisting in its stable interaction and protein modification by SMURF2. Results obtained from this study will help us establish a novel approach targeting EGFR, independent of a drug resistant EGFR mutation by altering its ubiquitination status via SMURF2 targeting. We anticipate that successful completion of this project will not only provide a better mechanistic insight exploring the roles of ubiquitination in EGFR protein stability, it will also provide a strong foundation for the development of peptidomimetic scaffold or small molecule inhibitor, which can disrupt EGFR-SMURF2 interaction to kill cancer cells and will be beneficial for certain patients.

Public Health Relevance

This project deals with developing a novel strategy to target EGFR, a widely accepted, druggable target in variety of epithelial cancers. In this project we want to establish the involvement of a ubiquitin ligase in EGFR protein stability and develop a novel strategy to target the ligase to degrade EGFR protein to kill EGFR- addicted cancer cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Krishnamurthy, Pranathi Meda; Shukla, Shirish; Ray, Paramita et al. (2017) Involvement of p38-?TrCP-Tristetraprolin-TNF? axis in radiation pneumonitis. Oncotarget 8:47767-47779
Elaimy, Ameer L; Ahsan, Aarif; Marsh, Katherine et al. (2016) ATM is the primary kinase responsible for phosphorylation of Hsp90? after ionizing radiation. Oncotarget 7:82450-82457
Ray, Paramita; Tan, Yee Sun; Somnay, Vishal et al. (2016) Differential protein stability of EGFR mutants determines responsiveness to tyrosine kinase inhibitors. Oncotarget 7:68597-68613
Ray, Dipankar; Cuneo, Kyle C; Rehemtulla, Alnawaz et al. (2015) Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy. Neoplasia 17:697-703
Cuneo, Kyle C; Nyati, Mukesh K; Ray, Dipankar et al. (2015) EGFR targeted therapies and radiation: Optimizing efficacy by appropriate drug scheduling and patient selection. Pharmacol Ther 154:67-77
Raghunathan, Krishnan; Ahsan, Aarif; Ray, Dipankar et al. (2015) Membrane Transition Temperature Determines Cisplatin Response. PLoS One 10:e0140925
Nyati, Shyam; Schinske-Sebolt, Katrina; Pitchiaya, Sethuramasundaram et al. (2015) The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-? signaling. Sci Signal 8:ra1
Shukla, Shirish; Allam, Uday Sankar; Ahsan, Aarif et al. (2014) KRAS protein stability is regulated through SMURF2: UBCH5 complex-mediated ?-TrCP1 degradation. Neoplasia 16:115-28
Ahsan, Aarif; Ramanand, Susmita G; Bergin, Ingrid L et al. (2014) Efficacy of an EGFR-specific peptide against EGFR-dependent cancer cell lines and tumor xenografts. Neoplasia 16:105-14
Ray, Dipankar; Shukla, Shirish; Allam, Uday Sankar et al. (2013) Tristetraprolin mediates radiation-induced TNF-? production in lung macrophages. PLoS One 8:e57290

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