Novel Compounds for Sensitization of Cancer Cells to EGFR Inhibitors

Method allowing to increase sensitivity and/or overcome resistance to EGFR inhibitors in cancer cells through inhibition of palmitoyltransferase DHHC20. 

Problem:

Inappropriate activation of the epidermal growth factor receptor (EGFR) contributes to a variety of human malignancies and correlates with poor prognosis and resistance to therapy. Whereas therapy targeting EGFR is currently approved for non-small cell lung carcinomas (NSCLC), advanced colorectal cancer, glioma, pancreatic carcinoma and head and neck tumors; triple negative breast cancer and NSCLC often show resistance to currently available therapies.

Solution:

Dr. Eric Witze’s lab at Penn has found that inhibition of palmitoyltransferase DHHC20 in cancer cells creates a dependence on EGFR signaling for cancer cell survival. Using a palmitoyltransferase inhibitor researchers demonstrated increased sensitivity to Gefitinib in EGFR-activated cancer cells as well as reversal of insensitivity to Gefitinib in lung cancer cells.
Using a series of bio- and chemo-informative approaches in collaboration with George Burslem's Lab at Penn, palmitoylation.  The compounds are being characterizing in cellular assays and optimized via structure activity relationship studies.

Advantages:

• Sensitization of drug-resistant cancers
• Potential reduction of the treatment doses and side-effects
• Potential use in recurrent cancer patients

Applications:

• Combinational therapy combining EGFR inhibitors and DHHC20 inhibitors

Stage of Development:

• Series of novel small molecules inhibiting EGFR palmitoylation

Desired Partnerships:

• Collaboration
• Co-development
• Drug discovery

Docket # 16-7601