Novel Mechanisms of Kinase Independent Pro-Survival Functions of EGFR in Cancer
Tyrosine kinase activity of epithelial growth factor receptor (EGFR) plays an important role in regulating numerous signaling pathways in cancer. It is commonly overexpressed in various cancers. Several strategies for cancer therapy were developed to target the kinase function of EGFR. However, the chemotherapeutic drugs against EGFR kinase functions developed either acquired resistance or innately resistant. Over past decade, few reports have demonstrated that EGFR possesses kinase-independent pro-survival functions. A better understanding of the molecular mechanisms involved in the kinase-independent pro-survival functions of EGFR bears a great potential for developing new strategies for cancer therapy. Therefore, this study was designed to further explore the molecular mechanisms underlying kinase-independent pro-survival functions of EGFR.
Earlier, we have reported autophagy induced by EGFR knockdown (loss-of-EGFR) caused cell death whereas autophagy induced by EGFR’s kinase inhibition caused growth arrest. The differences in autophagy mechanisms were unknown. In the first approach, we have shown that loss-of-EGFR causes selective mitophagy mediated by EGFR’s kinase-independent interaction with RICTOR and UT2 and activation of mTORC2/Akt signaling whereas inhibition of EGFR kinase function causes non-selective macro autophagy mediated by activation of mTORC1 signaling. To further support this, we have found an EGFR downregulating peptide demonstrating the induction of mitophagy and inhibition of tumor growth of orthotopic ovarian cancers in mice.
It was known that EGFR interacts with SGLT1 and stabilizes it in a kinase-independent manner to maintain the intracellular glucose concentration and inhibiting SGLT1 activity sensitized prostate cancer cells to EGFR TKIs. However, the role of SGLT1 in EGFR kinase inhibited conditions were not known. In the second approach of this dissertation, we have demonstrated that SGLT1 undergoes oligomerization and upon treatment with EGFR TKIs, enhances its oligomerization and upregulates sodium-dependent glucose transport. We also showed that increase in SGLT1 oligomerization was sustained in EGFR TKI resistant cells and inhibition of SGLT1 activity with phlorizin reduced the survival of resistant cells. It is concluded that enhanced SGLT1 activity mediated by oligomerization in EGFR TKI environment is another survival mechanism and may serve as a potential target for cancer therapy.