AACR 2018 – 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

Title

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 nertinib (N) irrespective of KRAS mutation (MT) status

Authors

Rekha Pal1, Nan Sing1, Ying Wang1, Ashok Srinivasan1, Peter C. Lucas1, Carmen J. Allegra1, Angela Davies2, Alshad S. Lani3, Samuel A.Jabobs1 and Katherine L. Pogue-Geile1
1 NSABP, Pittsburgh, PA; 2 Champions Oncology, Rockville, MD; 3 Puma Biotechnology, Inc. Los Angeles, CA

Abstract

KRAS mutant (MT) CRC tumors demonstrate constitutively activated RAF-MEK-ERK signaling pathways and are resistant to anti-EGFR therapies. In preclinical studies using KRAS MT CRC cell lines, resistance to MEK inhibitors (MEKi) lead 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 neratinib (N), but stem-like subtype cell lines were resistant regardless of KRAS MT status. In this study, we evaluated treatments with trametnib + neratinib in 6 PDX models (Champions Oncology). PDX models were characterized by their genomic signature for intrinsic subtypes, and molecularly profiled for KRAS, BRAF, PI3K, NRAS and DNA mismatch repair status (microsatellite instability-high, MSI-H; microsatellite stable, MSS).