Abstract 1937: YAP-TAZ-TEAD transcriptional program is a prominent driver of acquired resistance to KRASG12C-based therapies in patients with metastatic colorectal cancer
Authors: Coker Oluwadara , Sorokin Alexey , Akhave Neal , Pan Kelsey , Gao Fengqin , Liu Zhensheng , Kanikarla Preeti , Lee HeyMin , Villarreal Oscar , Alshenaifi Jumanah , Maddalena Giulia , Mohamed Alaa , Prescod Dionne , Menter David , Chowdury Saikat , Corcoran Ryan , Rai Kunal , Hong David , Kopetz Scott 
Published: March 2024

Abstract
Background: KRAS mutations are present in 50% of patients with metastatic colorectal cancer (mCRC) and play a critical role in mCRC tumor biology. KRASG12C mutations are present in 6% of patients with mCRC. While KRASG12C inhibitors (G12Ci) have entered the clinic, clinical responses to G12Ci are transient even when combined with EGFRi, highlighting the need to optimize therapeutic interventions. We have characterized our KRASG12C mCRC patient-derived xenograft (PDX) models and paired biopsies from progressing patients that have acquired resistance to G12Ci/G12Ci+EGFRi through an integrative multi-omics approach and have validated them through wet-lab experiments.
Experimental Procedures: qPCR analysis was performed on 13 PDX models that were established from paired tumor biopsies from patients pre and at progression of treatment. We also treated 5 KRASG12C mCRC PDX models with G12Ci +/- EGFRi until acquired resistance was achieved. Tumors were harvested post-treatment and whole-exome, RNAseq, and RPPA were performed on them. In parallel, 3 paired parental and G12Ci/EGFRi-resistant 2D/3D in vitro models were established and treated with G12Ci +/- EGFRi +/- pan-TEADi. Expression and response profiles were assessed through cell viability assays, western blot, qPCR, and IncuCyte analyses. We simultaneously re-established in vivo acquired resistance to G12Ci + EGFRi in 2 PDX models and treated them with pan-TEADi triple combo. Finally, we performed spatial transcriptomics (Xenium) from 6 paired pre-/post-treatment patient samples to characterize transcriptomic profiles at the single-cell resolution.
Results: In our PDX models, the acquisition of a new NRAS mutation and KRAS amplification in response to therapy were found, which are commonly known genomic resistance mechanisms to MAPK targeted therapies. 3 of the 5 PDX models (p &lt; 0.05, p &lt; 0.001) and 2 of 4 patients (p &lt; 0.01, p &lt; 0.001) from the PDX models established from paired tumor biopsies from patients pre and at progression of treatment exhibited YAP1-TEAD signaling as an acquired response to G12Ci-based therapies. In our in vitro work, pan-TEADi triple combo provided efficacy over G12Ci/therapy in 3D in vitro models while both 2D/3D in vitro resistant models were sensitized to pan-TEADi monotherapy, suggesting the combination drives a state change to be YAP dependent where YAP-TEAD signaling may now be driving MAPK signaling. Detailed spatial transcriptomic data will be presented.
Conclusion: Clinical responses to G12Ci are transient and require optimizing therapeutic modalities. In patients, where genomic mechanisms are not found, YAP-TAZ-TEAD signaling was found to be a common feature of resistance to inhibitors targeting the KRAS pathway. This work suggests that pan-TEADi may provide patients with improved therapeutic options.
Citation Format: Oluwadara Coker, Alexey Sorokin, Neal Akhave, Kelsey Pan, Fengqin Gao, Zhensheng Liu, Preeti Kanikarla, HeyMin Lee, Oscar Villarreal, Jumanah Alshenaifi, Giulia Maddalena, Alaa Mohamed, Dionne Prescod, David Menter, Saikat Chowdury, Ryan Corcoran, Kunal Rai, David Hong, Scott Kopetz. YAP-TAZ-TEAD transcriptional program is a prominent driver of acquired resistance to KRASG12C-based therapies in patients with metastatic colorectal cancer [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 1937.