Abstract LB-087: Inflammatory and stem-like colorectal cancer (CRC) subtypes identified in patient-derived xenograft (PDX) models show tumor growth inhibition (TGI) by the combination of trametinib (T) and neratinib (N) irrespective of KRAS mutation (MT) status
Authors: Pal Rekha , Song Nan , Wang Ying , Srinivasan Ashok , Lucas Peter C. , Allegra Carmen J. , Davies Angela M. , Lalani Alshad S. , Jacobs Samuel A. , Pogue-Geile Katherine L. 
Published: August 2018

Abstract
Background: KRAS MT CRC tumors demonstrate constitutively activated RAF-MEK-ERK signaling pathways and resistance to anti-EGFR therapies. In preclinical studies using KRAS MT CRC cell lines, resistance to MEK inhibitors (MEKi) led to induction of ERBB3. Using kinome-centered synthetic lethality screen, suppression of ERBB3 receptor tyrosine kinase is strongly synergistic with MEKi in CRC cell lines. We previously showed that KRAS MT cell lines of intrinsic inflammatory subtype were sensitive to MEKi and N, but stem-like subtype cell lines were resistant regardless of KRAS MT status. In this study, we evaluated treatment with T + N in 5 PDX models (Champions Oncology). PDX models were characterized by genomic signature for intrinsic subtypes, and molecularly profiled for KRAS, BRAF, PI3K, NRAS, and MSI status.
Methods: An initial study was performed for dose tolerability. Efficacy studies were undertaken with 10 mice in each of 4 cohorts: vehicle, N 40 mg/kg po qd , T 1.0 mg/kg po qd, and N 40 mg/kg + T 1.0 mg/kg. Doses were given until the model reached endpoint. Mean tumor volumes (MTV) of treatment groups were compared to control group to determine % tumor growth inhibition (TGI). Tissue specimens were obtained from vehicle and all treatment arms for WES, RNA seq, and phosphoprotein analysis.
Results:
Model NoSubtypeMT profile% TGI (T,N, T+N)*p-value v controlCTG-0117InflammatoryKRAS WT/MSS43% v 49% v 76%0.215 v 0.17 v 0.009CTG-0382InflammatoryKRAS MT/MSS62% v 40% v 80%0.009 v 0.11 v 0.001CTG-0406InflammatoryKRAS MT/MSS43% v 46% v 67%0.001 v 0.0006 v 0.0001CTG-0069Stem-likeKRAS MT/MSS39% v 32% v 61%0.12 v 0.31 v 0.015CTG-0079Stem-likeKRAS MT/MSS10% v 22% v 42%0.91 v 0.51 v 0.068
*TGI was determined by calculating % TGI (100% x [1-(final MTV − initial MTV of a treated group) / (final MTV – initial MTV of the control group)]).
Conclusions: T + N was well tolerated as evaluated by body weight and demonstrated TGI in all 3 inflammatory models and in 1 of two stem-like CRC PDX models. Importantly, these tumors were KRAS MT and MSS suggesting that T + N may be a promising targeted therapy for related CRC pts. WES, RNA seq, and phosphoprotein analyses from vehicle and treatment arms will be
performed. This analysis may define potential biomarkers related to sensitivity or resistance to T + N and inform additional targeted therapies.
Support: Champions Oncology; Puma Biotechnology
Citation Format: Rekha Pal, Nan Song, Ying Wang, Ashok Srinivasan, Peter C. Lucas, Carmen J. Allegra, Angela M. Davies, Alshad S. Lalani, Samuel A. Jacobs, Katherine L. Pogue-Geile. Inflammatory and stem-like colorectal cancer (CRC) subtypes identified in patient-derived xenograft (PDX) models show tumor growth inhibition (TGI) by the combination of trametinib (T) and neratinib (N) irrespective of KRAS mutation (MT) status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-087.