Abstract 1923: KRAS-mutant (mt) colorectal cancer (CRC) organoid models generated from patient-derived xenografts (PDX) show response to combination of trametinib (Tm), neratinib (N), and trastuzumab (Tz)
Authors: Pal Rekha , Srinivasan Ashok , Lucas Peter C. , Allegra Carmen J. , Davies Angela M. , Lalani Alshad S. , Jacobs Samuel A. , Pogue-Geile Katherine L. 
Published: August 2019

Abstract
Background: KRAS-mt CRC has constitutively activated RAF-MEK-ERK pathways and resistance to anti-EGFR therapies. In pre-clinical models, we found that cells with inflammatory subtype tumors were sensitive to the MEK-inhibitor, MEK162, plus N, regardless of KRAS mutations. However, both KRAS-mt and -wt stem-like CRC cells were resistant to this combination. In C-07 and C-08 clinical studies, patients (pts) with stem-like subtype tumors were resistant to chemotherapy and had a very poor prognosis. We hypothesized that dual-HER2 targeting may provide more robust ERBB inhibition than N alone. We therefore tested Tz combined with Tm+N using PDX organoids (PDXOs) derived from KRAS-mt CRC tumors. PDOs have emerged as powerful preclinical models to predict clinical outcomes. The goal of this study was to identify more efficacious drug combinations for KRAS-mt tumors and stem-like subtype tumors using PDXOs.
Methods: PDXO’s were generated using recently described methods from Hans Clevers' laboratory. Three KRAS-mt PDX tissues from Champions Oncology were used to generate four PDXOs for drug testing. The CTG-0406 PDX model was used to develop PDXOs from two different mice.
Results: All three KRAS-mt PDXOs: CTG-0406 (inflammatory), CTG-1170 (inflammatory), and CTG-0079 (stem-like), were resistant to Tm, N, and Tz, as single agents. N+Tz was effective in inhibiting cell viability in all four models; however, more significant viability inhibition occurred when Tm was added to N+Tz in three of the PDXOs including the stem-like model. In all PDXOs, Tm+N+Tz inhibited 67-76% viability.
Conclusion: We demonstrate that KRAS-mt PDXOs were inhibited to a greater extent with Tm+N+Tz compared to any of these drugs alone. PDXOs provide a rapid and cost-effective preclinical platform for screening of unique drug combinations for sensitivity or resistance.
Table 1.% PDXO cell viabilityDrugsCTG-0406 (1) (KRAS mt) InflammatoryCTG-0406 (2) (KRAS mt) InflammatoryCTG-1170 (KRAS mt) InflammatoryCTG-0079 (KRAS mt) Stem-LikeTm (10nM)96%116%95%94%N (125nM)109%97%96%92%Tz (20 µg/ml)92%119%97%93%Tm (10nM) + N (125nM)64%59%31%56%Tm (10nM) + Tz (20 µg/ml)74%75%41%70%N (125nM) + Tz (20 µg/ml)34%70%23%43%Tm (10nM) + N (125nM)+ Tz (20 µg/ml)26%33%24%31%
Support: NSABP Foundation, Inc.
Citation Format: Rekha Pal, Ashok Srinivasan, Peter C. Lucas, Carmen J. Allegra, Angela M. Davies, Alshad S. Lalani, Samuel A. Jacobs, Katherine L. Pogue-Geile. KRAS-mutant (mt) colorectal cancer (CRC) organoid models generated from patient-derived xenografts (PDX) show response to combination of trametinib (Tm), neratinib (N), and trastuzumab (Tz) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1923.