Inhibition of the endosomal recycling pathway downregulates HER2 activation and overcomes resistance to tyrosine kinase inhibitors in HER2-positive breast cancer. (31st March 2022)

• Record Type: Journal Article
• Authors: Mishra, Anurag; Hourigan, David; Lindsay, Andrew J.
• Is Part Of: Cancer letters. Volume 529(2022)
• Page Start: 153
• Page End: 167
• Publication Date: 2022-03-31
• Subjects: Endosomal recycling pathway -- HER2-targeted therapies -- Drug synergy -- Drug resistance -- Primaquine; RCP Rab coupling protein -- RTK Receptor tyrosine kinase -- TKI Tyrosine kinase inhibitor; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2022.01.003
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The development of HER2-targeted therapies has led to a dramatic improvement in outcomes for breast cancer patients. However, nearly all patients with metastatic HER2-positive breast cancer will eventually progress on these therapies due to innate or acquired resistance. Recent evidence suggests that the endosomal recycling of HER2 plays an important role in regulating its oncogenic signalling. Here we report that the expression of Rab coupling protein (RCP), a key regulator of endosomal recycling, positively correlates with that of HER2 and HER3 in breast tumours, and high RCP expression is predictive of poor relapse-free and overall survival in patients with HER2-amplified breast cancer. Chemical and genetic inhibition of endosomal recycling leads to a reduction in the total cellular levels of HER2 and HER3 and inhibits the activation of their downstream signalling pathways. We find that HER2 and HER3 that have been internalised from the plasma membrane are diverted to lysosomes for degradation when endosomal recycling is blocked. Primaquine (PQ), a small molecule inhibitor of the endosomal recycling pathway, synergises with HER2-targeting tyrosine kinase inhibitors and overcomes innate and acquired resistance to these TKIs. Moreover, TKI-induced drug tolerant persister cells are vulnerable to endosomal recycling inhibitors. These findings suggest that inhibition of endosomal recycling represents a promising therapeutic strategy for treating drug resistant HER2-positive breast cancer. Highlights: Inhibition of the endosomal recycling pathway downregulates the levels and activation of HER2 and HER3. Endosomal recycling inhibitors synergise with HER2-targeting therapies. Drug resistant HER2-positive breast cancer cells are vulnerable to endosomal recycling inhibitors. The endosomal recycling pathway is a novel and underexploited target for the development of new anti-cancer therapies.