Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1

Area of Science:

• Cell Biology
• Molecular Oncology
• Signal Transduction

Background:

• Oncogenic mutations in Epidermal Growth Factor Receptor (EGFR) drive cancer by promoting constitutive activation and aberrant signaling.
• EGFR mutations activate mechanistic target of rapamycin complex 1 (mTORC1) signaling, increasing cell proliferation, but kinase-independent roles are emerging.
• EGFR's role in cell survival and cancer progression extends beyond its kinase activity, necessitating a deeper understanding of its functions.

Purpose of the Study:

• To investigate a novel, kinase-independent mechanism of mTORC1 activation by EGFR.
• To elucidate the role of EGFR's lysosomal localization in mTORC1 activation.
• To explore therapeutic strategies targeting both kinase and non-kinase functions of mutant EGFR.

Main Methods:

• Investigated EGFR's interaction with Rheb at the lysosome.
• Utilized genetic knock-in models (EGFR-E804K) to assess Rheb-GTP levels and mTORC1 activation.
• Evaluated the efficacy of tyrosine kinase inhibitors (afatinib, erlotinib) and a novel small molecule (BIEGi-1) targeting EGFR functions.

Main Results:

• EGFR directly activates mTORC1 independently of its kinase activity through physical binding to Rheb at the lysosome.
• EGFR's Glu804 residue is crucial for its guanine exchange factor (GEF) activity towards Rheb.
• Genetic disruption of EGFR's GEF activity (EGFR-E804K) significantly reduced mTORC1 activation, cell proliferation, and tumor growth.
• Afatinib demonstrated superior inhibition of mTORC1 and cell growth compared to erlotinib by blocking both kinase and GEF activities.
• The novel small molecule BIEGi-1, targeting both EGFR activities, potently inhibited the viability of EGFR-mutant cancer cells.

Conclusions:

• EGFR possesses a critical, kinase-independent function in activating mTORC1 via Rheb GEF activity at the lysosome.
• Targeting both the kinase and Rheb-GEF activities of mutant EGFR represents a potent therapeutic strategy for cancers driven by EGFR mutations.
• This discovery provides a fundamental insight into cell growth regulation and opens new avenues for rational drug design in oncology.