Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth

Abstract

IntroductionHuman epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treatment of breast cancer. Thus, agents that reduce HER3 expression at the plasma membrane may synergize with current therapies and offer a novel therapeutic strategy to improve treatment.MethodsWe devised an image-based screening platform using membrane localized HER3-YFP to identify small molecules that promote HER3 internalization and degradation. In vitro and in vivo tumor models were used to characterize the signaling effects of perhexiline, an anti-anginal drug, identified by the screening platform.ResultsWe found perhexiline, an anti-anginal drug, selectively internalized HER3, decreased HER3 expression, and subsequently inhibited signaling downstream of HER3. Consistent with these results, perhexiline inhibited breast cancer cell proliferation in vitro and tumor growth in vivo.ConclusionsThis is the first demonstration that HER3 can be targeted with small molecules by eliminating it from the cell membrane. The novel approach used here led to the discovery that perhexiline ablates HER3 expression, and offers an opportunity to identify HER3 ablation modulators as innovative therapeutics to improve survival in breast cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0528-9) contains supplementary material, which is available to authorized users.

The anti-HER3 (ErbB3) therapeutic antibody 9F7-F11 induces HER3 ubiquitination and degradation in tumors through JNK1/2- dependent ITCH/AIP4 activation

“…A mixture of anti-EGFR monoclonal antibodies that target different EGFR epitopes and increase EGFR ubiquitination and degradation in a CBL-independent manner led to improved efficacy of anti-EGFR therapy [24]. Finally, small molecules, such as the anti-anginal drug perhexilline, promote HER3 internalization and further ubiquitination, leading to inhibition of tumor growth [56]. …”

Mitochondrial Metabolism in PDAC: From Better Knowledge to New Targeting Strategies

“…In particular, most of the attention is focused on the rate-limiting enzyme of FAO, the carnitine palmitoyltransferase 1 (CPT1). CPT1 can be pharmacologically targeted by drugs like Etomoxir and Perhexiline or the novel compound Avocatin B, with promising results in vitro and in preclinical studies [135,[138][139][140][141][142].…”

Perhexiline maleate enhances antitumor efficacy of cisplatin in neuroblastoma by inducing over-expression of NDM29 ncRNA

“…Although perhexiline maleate has been reported to be a calcium antagonist it was demonstrated that this drug concurrently administrated with doxorubicin also enhanced doxorubicin inhibition of proliferation of the anthracycline-resistant P388 cell sub-line in a reversible way 20 21 . Recently, it has been reported that perhexiline is also a HER3 ablation modulator that inhibits breast cancer cell proliferation in vitro and in vivo, having a synergistic inhibitory effect with lapatinib on tumor growth 34 . Nonetheless, the anti-cancer mechanism of perhexiline remains still unclear.…”