ITF2357

HDAC inhibitor ITF2357 reduces resistance of mutant-KRAS non-small cell lung cancer to pemetrexed through a HDAC2/miR-130a-3p-dependent mechanism

Background: Histone deacetylases (HDACs) play a role in oncogenic processes, making their inhibitors a potential strategy for cancer treatment. In this study, we investigated the mechanism by which the HDAC inhibitor ITF2357 addresses the resistance of mutant (mut)-KRAS non-small cell lung cancer (NSCLC) to pemetrexed (Pem).

Methods: We first assessed the expression of HDAC2 and Rad51, both associated with NSCLC tumorigenesis, in NSCLC tissues and cell lines. We then examined the impact of ITF2357 on Pem resistance in the wild-type KRAS NSCLC cell line H1299, the mut-KRAS cell line A549, and the Pem-resistant mut-KRAS cell line A549R, both in vitro and in xenograft models using nude mice.

Results: We found that HDAC2 and Rad51 expression was elevated in NSCLC tissues and cells. ITF2357 was shown to downregulate HDAC2, thereby reducing resistance to Pem in H1299, A549, and A549R cells. Moreover, HDAC2 was found to bind to miR-130a-3p, leading to the upregulation of its target gene Rad51. The in vitro results were confirmed in vivo, where ITF2357 inhibited the HDAC2/miR-130a-3p/Rad51 pathway, ultimately decreasing the resistance of mut-KRAS NSCLC to Pem.

Conclusion: Overall, ITF2357 restores miR-130a-3p expression by inhibiting HDAC2, which represses Rad51 and reduces the resistance of mut-KRAS NSCLC to Pem. Our findings suggest that ITF2357 may serve as a promising adjuvant strategy to enhance the sensitivity of mut-KRAS NSCLC to pemetrexed.