Abstract 3101: Evaluation of novel therapeutic strategies for KRAS mutated NSCLC patients using our own collections of PDX and PDX-derived organoids
Authors: Yagüe Patricia , Gomez David , Ucero Álvaro C , García Laura , Plaza Patricia , Carrizo Nuria , Solorzano José Luis , Paz-Ares Luis , Ferrer Irene 
Published: June 2022

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the most frequent mutated driver gene in NSCLC but today has no effective treatments. Therefore, there is an urgent unmet need to find a tailored treatment alternative in the clinic. We need experimental models which really predict the efficacy of these alternative treatments. PDX and organoids are models that recapitulate more accurately the complexity of human cancer, therefore they are the best models we can use to address such clinically relevant questions. We aim to generate and characterize both NSCLC PDX, and PDX-derived organoids (PDXDOs) collections to perform preclinical assays, address to find alternative therapies for KRAS-mutant lung cancer. Among these therapeutic strategies we evaluated the efficacy of CDK4 inhibitors (CDK4i) in combination with ERK1/2 inhibitors (ERK1/2i). We studied the mechanism of action of the drugs in combination and identified possible predictive response biomarkers by RNAseq. We have established and characterized a collection of 45 NSCLC PDX models derived from early-stage patients, eight of them with KRAS mutations. All retained the principal histologic and molecular characteristics of their donors during the passages. We have also generated a collection of 15 PDXDOs, which maintained the same characteristics of their PDX donors. We evaluate the efficacy of CDK4i in monotherapy and in combination with ERK1/2i in KRAS-mutated models. In vitro, using PDXDOs, the therapeutic combination tested reduced viability and downregulated signaling pathways involved in cell progression, this effect was observed in all PDXDO models tested, including those that were primary resistant to CDK4i in monotherapy. Similarly, in vivo, using the PDX models, the therapeutic combination tested produced a significant reduction in tumor growth compared to the drugs in monotherapy. The transcriptomic analysis showed CDK4i inhibited cell-cycle processes, whereas the combination therapy resulted in an increased inhibition and also reversed the CDK4i-mediated activation of PI3K or WNT pathways, which would explain the synergistic effect of the combination. In conclusion, we have established a collection of 45 NSCLC PDX models and 15 PDXDOs, which allow to evaluate (in vitro and in vivo) the therapeutic efficacy of different drug combinations targeting different driver genes mutated such KRAS, which today has no effective treatments. These preclinical models will be really useful to integrate drug screening with biomarker discovery. Using our collections, we have demonstrated the combination of CDK4i with ERK1/2i was more effective than the drugs in monotherapy, even for those cases which primary showed CDK4i-resistance. Therefore, we propose this therapeutic combination as a good therapeutic strategy to test in the clinic.
Citation Format: Patricia Yagüe, David Gomez, Álvaro C Ucero, Laura García, Patricia Plaza, Nuria Carrizo, José Luis Solorzano, Luis Paz-Ares, Irene Ferrer. Evaluation of novel therapeutic strategies for KRAS mutated NSCLC patients using our own collections of PDX and PDX-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3101.