Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Receptor tyrosine kinase (RTK) hyperactivation of the MAPK/Erk pathway drives numerous diseases, including cancer.
• Current therapeutic strategies targeting this pathway have limited long-term success.
• Erk is normally sequestered by the adaptor protein Shc to prevent aberrant signaling.

Purpose of the Study:

• To develop a novel strategy for inhibiting MAP kinase signal transduction.
• To identify compounds that preserve the Shc-Erk complex upon RTK activation.
• To block the interaction between Shc phosphotyrosine binding (PTB) domain and RTKs like EGFR and ErbB2.

Main Methods:

• Computational screening of a drug library to find hits binding to Shc^PTB.
• In vitro validation of identified compounds.
• Cellular efficacy studies in cancer cells.

Main Results:

• Indomethacin, a non-steroidal anti-inflammatory drug, was identified as a primary hit.
• Indomethacin demonstrated proof of principle for pathway down-regulation.
• The study identified a potential optimizable lead compound for cancer therapy.

Conclusions:

• Preserving the Shc-Erk complex offers a novel approach to inhibit RTK-mediated signaling.
• Indomethacin serves as a lead compound for developing new cancer therapeutics targeting the MAPK/Erk pathway.