Abstract A173: Potent anti-tumor activity of entrectinib in patient-derived models harboring oncogenic gene rearrangements of NTRKs
Authors: Li Gang , Kim Seung Tae , Kim Kyoung-Mee , Lee Jeeyun , Russo Mariangela , Misale Sandra , Bardelli Alberto , Patel Roopal , Cam Nicholas , Wei Ge , Boomer Aaron , Murphy Danielle , Christiansen Jason , Shoemaker Robert , Hornby Zachary , Wild Robert 
Published: May 2016

Abstract
The Trk family of kinases, which include TrkA, TrkB and TrkC, encoded by NTRK1, NTRK2 and NTRK3, respectively, are high affinity receptors for the neurotrophin family of nerve growth factors. Dysregulated kinase activity of Trk family members due to chromosome rearrangements has been shown to be an oncogenic driver in a number of cancer types, including lung, colorectal, salivary gland, papillary thyroid, glioblastoma, melanoma and other tumors. Although the prevalence of such events is relatively low in most tumor types (&lt;2%), the number of new fusion partners and the list of tumor types that are found to harbor these driver fusions have been steadily increasing. The significant unmet medical need and the relatively low frequency of fusion incidents require an integrated therapeutic/diagnostic (Rx/Dx) approach to best serve the patients in need.
Entrectinib (formerly RXDX-101) is an orally available, potent and selective ATP-competitive pan-Trk, ROS1 and ALK inhibitor, with comparable, low nanomolar potency against kinase activity of TrkA, TrkB and TrkC in biochemical and cell based assays. In engineered BaF3 cells expressing clinically identified Trk fusion proteins, with various partners, entrectinib demonstrated potent anti-proliferative activity in the range of 2-5 nM, accompanied by inhibition of Trk phosphorylation and concomitant inactivation of downstream effectors such as PLCγ1, AKT and ERK. The clinical relevance of targeting Trk fusions by entrectinib was further demonstrated by several in vitro and in vivo studies involving patient-derived tumor cells (PDCs) and patient-derived xenografts (PDXs) determined to harbor (by NGS and FISH) and express (by IHC) Trk rearrangements. In 2-dimensional and 3-dimensional proliferation assays, entrectinib effectively inhibited proliferation of PDCs from a CRC patient positive for TPM3-NTRK1 fusion. In another independent study, entrectinib, at exposures significantly lower than clinically achievable levels, caused tumor regression in a PDX derived from a CRC patient positive for LMNA-NTRK1 fusion. All the functional readouts were correlated with changes in target and pathway biomarkers.
In conclusion, our preclinical data demonstrate the potential of entrectinib as an effective treatment for Trk-fusion driven tumors of multiple histologies, which is now being demonstrated in ongoing clinical trials.
Citation Format: Gang Li, Seung Tae Kim, Kyoung-Mee Kim, Jeeyun Lee, Mariangela Russo, Sandra Misale, Alberto Bardelli, Roopal Patel, Nicholas Cam, Ge Wei, Aaron Boomer, Danielle Murphy, Jason Christiansen, Robert Shoemaker, Zachary Hornby, Robert Wild. Potent anti-tumor activity of entrectinib in patient-derived models harboring oncogenic gene rearrangements of NTRKs. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A173.