While HER2 and EGFR are overexpressed in breast
cancers and multiple other types of
tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many
cancer patients, largely because
cancers acquire resistance to HER2/EGFR-specific drugs.
Cancers that overexpress the HER-family
proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of
disulfide bond formation by
Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with
proline isomerization in HER2/EGFR overexpressing cells also induces
cancer cell death. The peptidyl-
prolyl isomerase inhibitor
Cyclosporine A (CsA) selectively kills EGFR+ or HER2+
breast cancer cells in vitro by activating
caspase-dependent apoptotic pathways. Further, CsA synergizes with the
DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+
tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+
cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill
cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.