Tyrosine 211 (Y211) phosphorylation of proliferation cell
nuclear antigen (
PCNA) coincides with pronounced
cancer cell proliferation and correlates with poor survival of
breast cancer patients. In
epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitor (TKI)-resistant cells, both nuclear EGFR (nEGFR) expression and
PCNA Y211 phosphorylation are increased. Moreover, the resistance to EGFR TKI is a major clinical problem in treating EGFR-overexpressing
triple-negative breast cancer (TNBC). Thus, effective treatment to combat resistance is urgently needed. Here, we show that treatment of cell-penetrating
PCNA peptide (
CPPP) inhibits growth and induces apoptosis of human TNBC cells. The Y211F
CPPP specifically targets EGFR and competes directly for
PCNA tyrosine Y211 phosphorylation and prevents nEGFR from binding
PCNA in vivo; it also suppresses
tumor growth by sensitizing EGFR TKI resistant cells, which have enhanced nEGFR function and abrogated classical EGFR membrane signaling. Furthermore, we identify an active motif of
CPPP, RFLNFF (RF6
CPPP), which is necessary and sufficient to inhibit TKI-resistant TNBC cell growth of orthotopic implanted
tumor in mice. Finally, the activity of its synthetic retro-inverted derivative, D-RF6
CPPP, on an equimolar basis, is more potent than RF6
CPPP. Our study reveals a
drug candidate with translational potential for the future development of safe and effective therapeutic for EGFR TKI resistance in TNBC.