entrectinib and Pancreatic-Neoplasms

The advent of molecular biology resulted in the discovery of new oncogenes that have led to the development of targeted therapies for the management of cancer patients. The development of these therapies has improved the prognosis of patients in various tumour localizations. The TRK receptor (tropomyosin receptor kinase) is a transmembrane receptor with a tyrosine kinase activity that plays a role in both cell proliferation and the physiology of the nervous system. Fusions involving the NTRK gene, which codes for this receptor, have been found in different types of solid tumours and lead to its constitutional activation. These fusions, however uncommon, are mainly found in rare pediatric tumours but can also be encountered in digestive cancers with high prevalence (such as colorectal cancer, especially in case of microsatellite instability, with a frequency of 2.5 to 38.5 %) or in aggressive cancers (such as pancreatic cancer). Therapies targeting TRK, such as larotrectinib or entrectinib, have shown significant response rates, usually greater than 6 months, for tumours from various primary sites presenting NTRK fusions and refractory to standard therapies. These fusions can be detected by different methods: immunohistochemistry, FISH (fluorescence in situ hybridization) as well as NGS (next generation sequencing). The intent of this review is to report on current knowledge on NTRK fusions in oncology and to discuss the role of these fusions in digestive cancers and potential therapeutic implications.

Topics: Benzamides; Colorectal Neoplasms; Gastrointestinal Neoplasms; Gene Fusion; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; In Situ Hybridization; Indazoles; Membrane Glycoproteins; Nerve Growth Factors; Oncogene Proteins; Oncogene Proteins, Fusion; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Receptor, trkA; Receptor, trkB; Receptor, trkC

NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drug-resistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.

Topics: Animals; Apoptosis; Bcl-2-Like Protein 11; Benzamides; Cell Line, Tumor; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; ErbB Receptors; Female; HEK293 Cells; Humans; Indazoles; Lung Neoplasms; Male; Mice, Inbred NOD; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Neoplasms; Pancreatic Neoplasms; Protein Kinase Inhibitors; Receptor, trkA