Re-examining HSPC1 inhibitors
HSPC1 plays a pivotal role in the development and progression of various cancers, including colorectal cancer (CRC). However, clinical trial outcomes assessing the effectiveness of HSPC1 inhibitors across different cancer types have been less promising than anticipated. Additionally, certain N-terminal inhibitors show greater success than others, despite targeting similar mechanisms. This study investigates the impact of three N-terminal HSPC1 inhibitors—17-DMAG, NVP-AUY922, and NVP-HSP990—on CRC cells, focusing on their effects on client protein levels over time. The inhibitors were also tested in combination with commonly used CRC chemotherapeutic agents (5-fluorouracil, oxaliplatin, and irinotecan). Given the anti-apoptotic roles of HSPA1A and HSPB1, gene silencing was employed to assess the contribution of these proteins to resistance against HSPC1 inhibitors and chemotherapeutic drugs.
The study revealed notable differences in the degradation patterns of key client proteins when comparing the three inhibitors. These differences were also evident in combination treatments—17-DMAG was more effective than NVP-AUY922 in enhancing the cytotoxicity of 5-fluorouracil, oxaliplatin, and irinotecan. Overall, the findings highlight distinct variations among N-terminal HSPC1 inhibitors, despite their shared mechanism of action. Although all three inhibitors induced significant levels of the anti-apoptotic proteins HSPA1A and HSPB1, silencing these proteins did not enhance sensitivity to HSPC1 inhibition. The results suggest that HSPC1 inhibitors can enhance the efficacy of chemotherapeutic agents in CRC, offering potential for clinical trials. However, from a clinical perspective, variability in individual patient responses to these inhibitors may be considerable.