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Combining HDAC6 inhibitors with KRAS inhibitors for the treatment of Non-Small Cell Lung Cancer (NSCLC)

Non-small cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases. Approximately 30% of NSCLC patients harbour a KRAS-mutation, and 14% of these patients have a co-occurring LKB1-mutation. NSCLC patients that present with this genotype are significantly correlated with poor clinical outcomes, and their survival rate is only 9–12 . Hence, this group of patients have a distinct unmet need and new treatment options are urgently needed. The main aim of this project is to establish a new treatment-regimen for these patients.
The applicant recently discovered a new role for histone deacetylase 6 (HDAC6) in the control of cancer cell metabolism. Moreover, the applicant revealed enhanced response to HDAC6-inhibition (HDAC6i) in KRAS/LKB1 pre-clinical animal models, which can be attributed to metabolic vulnerabilities in this genotype of NSCLC. Separately, early this year, the first KRAS-inhibitors (KRASi) were approved for the treatment of KRAS-driven NSCLC. Interestingly, clinical data revealed that in advanced NSCLC patients with KRAS and co-occurring LKB1 mutations there is an improved response to KRASi. Patients with co-mutations in LKB1(n=14) had an overall response rate (ORR) of 64% compared with 33% in those with wild-type tumours (n=30).
We believe that given the increased response of KRAS/LKB1 NSCLC to KRASi and HDAC6i, as well as the well documented role of KRAS in controlling cancer cell metabolism, that testing the combination of these drugs could be a viable option for this group of patients. The applicant has preliminary in vitro data demonstrating a clear synergistic effect of combining HDAC6i and KRASi. Here, we aim to use pre-clinical animal models to test this combination regimen, while also examining the metabolic and immunological effect. This project is highly likely to result in a phase 1 clinical trial and ultimately a new treatment option for a group of patients who currently are underserved.