The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer

Abstract

Breast cancer is the leading cause of cancer-related death in women worldwide. Human epidermal growth factor receptor 2 (HER2)-positive subtype comprises 20% of sporadic breast cancers and is an aggressive disease. While targeted therapies have greatly improved its management, primary and acquired resistance remain a major roadblock to making it a curable malignancy. Ganetespib, an Hsp90 (Heat shock protein 90) small molecule inhibitor, shows preferential efficacy in HER2-positive breast cancer, including therapy-refractory cases, and has an excellent safety profile in ongoing clinical trials (38 in total, six on breast cancer). However, Ganetespib itself evokes acquired resistance, which is a significant obstacle to its clinical advancement. Here, we show that Ganetespib potently, albeit temporarily, suppresses HER2-positive breast cancer in genetic mouse models, but the animals eventually succumb via acquired resistance. We found that Ganetespib-resistant tumors upregulate several compensatory HSPs, as well as a wide network of phospho-activated receptor tyrosine kinases (RTKs), many of which are HSP clients. Downstream of p-RTKs, the MAPK pathway remains suppressed in the resistant tumors, as is HER2 itself. In contrast, the p-RTK effector Akt is stabilized and phospho-activated. Notably, pharmacological inhibition of Akt significantly delays acquired Ganetespib resistance, by 50%. These data establish Akt as a unifying actionable node downstream of the broadly upregulated HSP/p-RTK resistance program and suggests that Akt co-targeting with Ganetespib may be a superior therapeutic strategy in the clinic.