Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small molecule tyrosine kinase inhibitors (TKIs) is often ineffective in treating cancers harboring wild-type EGFR (wt-EGFR). TKIs are known to cause dimerization of EGFR without altering its expression level. 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， using wt-EGFR-expressing cancer cells A549 (lung)， DU145 (prostate)， PC3 (prostate)， and MDA-MB-231 (breast)， we characterized the TKI-induced dimerization status of EGFR and determined the dependency of cells on kinase-inactivated EGFR for survival. We report that TKI-induced EGFR dimerization is dependent on palmitoylation and independent of its kinase activity， and that mutations of the cysteine residues known to be critical for EGFR's palmitoylation abolished TKI-induced EGFR dimerization. Furthermore， TKI-induced EGFR dimerization is persistent in TKI-resistant cells， and inhibition of palmitoylation by 2-bromopalmitate， or targeted reduction of the kinase-inactivated EGFR by siRNA or by an EGFR-downregulating peptide， are lethal to TKI-resistant cancer cells. This study suggests that 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.