Abstract 1976: Targeting metabolism in non-small cell lung cancer (NSCLC) with the novel multitarget small molecule PI3K-CDK4/6-CDK9 inhibitor LCI139
Authors: McHale Cody C. , Foureau Anna V. Ivanina , Dryden Hailey L. , Maddeboina Krishnaiah , Pal Dhananjaya , Yada Bharath , Arditti Page Mangum , Guo Fei , Mileham Kathryn F. , Foureau David M. , Durden Donald L. 
Published: March 2024

Introduction: NSCLC is a heterogenous disease estimated to cause the majority of all 2023 United States cancer-related deaths. There is no broadly applicable targeted therapy to treat lung cancer and those FDA-approved drugs target patient-specific biomarker mutations such as EGFR, ALK, ROS1, etc. Targeting multiple oncogenic pathways to induce synthetic lethality is an attractive strategy for anticancer therapeutic development. Here, we describe the effects of novel multitarget small molecule PI3K-CDK4/6-CDK9 inhibitor LCI139 on a panel of human NSCLC cells of mixed histologic and mutational backgrounds.

Methods: LCI139 specific target inhibition was assessed by cell-free kinase hotspot/lipid kinase assay and KINOMEscan. LCI139 (0.001-10μM) was screened against NCI-H1975, NCI-H1703, NCI-H1373, NCI-H1781 and NCI-H226 human cell lines; IC50 values determined by CellTiter-Glo/WST-8 Assay and apoptotic rate by flow cytometry (Annexin V/7-AAD). Metabolomic profile of representative LCI139 sensitive (LCI139S) and resistant (LCI139R) NSCLC cells was evaluated by western blot.

Results: LCI139 is a highly potent inhibitor of PI3K-CDK4/6-CDK9: 0.070µM (PI3Kα), 0.461µM (PI3Kγ), 0.214µM (PI3Kδ), 0.0015µM (CDK4), 0.0036µM (CDK6), 0.000039µM (CDK9). NCI-H1703, NCI-H226, NCI-H1373 and NCI-H1975 were highly sensitive to LCI139 (0.68, 3.2, 35.27 and 342.4nM IC50), while NCI-H1781 remained insensitive up to 10μM. Confirming those findings, LCI139 promoted robust apoptotic cell death in NCI-H1703, NCI-H226, NCI-H1373 and NCI-H1975 but not NCI-H1781. LCI139S H1703 cells displayed increased bioenergetic reliance on oxidative phosphorylation (OXPHOS), compared with the LCI139R H1781 cells. In the LCI139S H1703 cells, LCI139 treatment decreased expression of all mitochondrial complexes (I-IV) and glycolytic enzymes (HK2, GAPDH, LDHA). Conversely, LCI139 treatment of LCI139R H1781 cells only inhibited expression of mitochondrial complexes II and III, but increased glucose uptake (Glut1) and retained expression of other glycolytic enzymes.

Conclusions: Triple PI3K-CDK4/6-CDK9 inhibitor LCI139 is nanomolar potent against several NSCLC cells lines of mixed histologic and mutational backgrounds. NSCLC cells that are most reliant on OXPHOS to generate ATP, a classic metabolic adaptation to chemotherapy, appear to be most sensitive to LCI139. Taken together, these data support further drug characterization and mechanistic dissection to assess LCI139’s potential clinical utility in treating advanced stage and recurrent NSCLC.

Citation Format: Cody C. McHale, Anna V. Ivanina Foureau, Hailey L. Dryden, Krishnaiah Maddeboina, Dhananjaya Pal, Bharath Yada, Page Mangum Arditti, Fei Guo, Kathryn F. Mileham, David M. Foureau, Donald L. Durden. Targeting metabolism in non-small cell lung cancer (NSCLC) with the novel multitarget small molecule PI3K-CDK4/6-CDK9 inhibitor LCI139 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1976.