Abstract 7205: Targeting diverse pathways for the treatment of KRAS driven non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases. 32% of patients with NSCLC harbour a KRAS mutation, and these patients have poor clinical outcomes. The newly approved KRAS inhibitors (KRASi) have shown clinical promise, however most patients eventually develop resistance. Hence, it is critical to understand the mechanism of resistance to KRAS inhibition to fuel effective combinational therapy strategies. We recently demonstrated enhanced sensitivity to Histone deacetylase 6 (HDAC6) inhibitors (HDAC6i) in KRAS driven NSCLC. Hence, we sought to explore the benefit of combining HDAC6i with KRASi in KRAS driven NSCLC. Using two separate cell viability assays, we demonstrated a synergistic response to the KRASi and HDAC6i in combination in KRAS driven NSCLC cell lines. Moreover, we observed a decrease in the migration rate with this combination in comparison to the single drug treatment. We also demonstrated a significant reduction in colony formation following the combination of KRASi and HDAC6i. Finally, we confirmed enhanced sensitivity to this drug combination in three-dimensional (3D) cell cultures. To further decipher the specific mechanism of action of HDAC6 in KRAS driven NSCLC we performed a co-immunoprecipitation of HDAC6 in NSCLC cell lines and analysed by liquid-chromatograph mass spectrometry (LC/MS). We found several epithelial-to-mesenchymal transition (EMT) associated proteins such as Yes Association Protein (YAP) and Vimentin (VIM) bound to HDAC6 in KRAS driven NSCLC cells. Interestingly, bulk RNA sequencing revealed a down-regulation of the EMT pathway in cells treated with a HDAC6i compared to the control. Specifically, in this data, YAP and VIM were down regulated following treatment with HDAC6i, among other EMT markers such as Snai1, Twist, and Zeb1/2. Interestingly, we observe a significant reduction in response to HDAC6i in NSCLC cells overexpressing YAP. Given this data combined with recent literature demonstrating an upregulation of EMT proteins associated with KRAS resistances, we purpose that HDAC6 inhibition could be a mechanism to overcome KRAS resistance. In conclusion, we have demonstrated HDAC6i and KRASi as an effective combination strategy for KRAS driven NSCLC. We also propose that the mechanism of action may be through HDAC6’s regulation of EMT, and this may help overcome resistance to KRASi, however this warrants further investigation. Citation Format: Robyn Stanley, Saoirse Flanagan, Sze Ying Tan, Eugene Dillion, Amanda P. Armstrong, Jarushka Naidoo, Kwok-kin Wong, Gerard Cagney, Triona Ni Chonghaile, Catriona M. Dowling. Targeting diverse pathways for the treatment of KRAS driven non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7205.