The Role of Kinase Inactive EGFR in Cancer Cell Survival



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Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small molecule tyrosine kinase inhibitors (TKIs) are often ineffective in treating cancers harboring wild-type (wt) EGFR. Given the fact that EGFR possesses kinase independent pro-survival function, the role of TKI inactivated EGFR in cancer cell survival needs to be addressed. In this study, we chronically treated wt EGFR expressing cancer cells, A549 (lung), DU145 (prostate), PC3 (prostate), and MDA-MB231 (breast), with TKIs until they acquired resistance to treatment. The primary focus of this thesis was to then to 1) characterize both the kinase activity and TKI induced dimerization status of EGFR in TKI resistant cells, 2) elucidate the biochemical nature of TKI induced EGFR dimers, and 3) determine the dependence of TKI resistant cells on kinase inactivated EGFR for survival.

A substantial inhibition of EGFR’s phosphorylation/activation status coupled with an increase in TKI induced membrane tethered EGFR dimerization were observed in the TKI resistant cells. We demonstrated that TKI-induced EGFR dimerization is dependent on palmitoylation, independent of EGFR’s kinase activity, and mutations of cysteine residues known to be critical for EGFR’s palmitoylation abolished TKI-induced EGFR dimerization. Disruption of TKI induced dimerization by inhibition of palmitoylation, or targeted reduction of the kinase inactivated EGFR by siRNA or by an EGFR downregulating peptide were observed to be lethal to TKI resistant cancer cells. Taken together, the data presented in this thesis suggests that the kinase-inactivated EGFR remains to be a viable therapeutic target for wt EGFR cancers and that inhibiting palmitoylation or downregulating EGFR may overcome TKI resistance.



EGFR, Tyrosine kinase inhibitors, Dimerization, Palmitoylation, Kinase independent function, Resistance