Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro

Abstract

Abstract. In the prostate, cellular growth and differentiation are finely regulated by a complex interaction between stromal and epithelial cells under the control of both autocrine and paracrine regulatory factors such as the nerve growth factor (NGF). However, the role of NGF and its receptors including the high-affinity p-140 TrkA and the low-affinity p75 NTR receptors remains controversial. Moreover prostate tissues stored other neutrophins such as NT3, NT4 and brain derived neutrophic factor (BDNF) as well as the corresponding receptors (NTRs). Different members of NTRs are expressed during prostate cancer (PCa) progression, suggesting their involvement in cell proliferation, anoikis protection and malignancy. Therefore, we analyzed the expression of NTRs including NTRK1 (TrkA), NTRK2 (TrkB), NTRK3 (TrkC) and p75 NGFR in a panel of 7 well-characterized PCa cell lines and 12 cell derivatives from PC3 (4), DU145 (2), CWR22R (4) and LnCap (2) cell lines possessing different proliferative/ invasive capabilities. We evaluated also the role of NGF, BDNF and NT3 in the modulation of cell migration and invasion and, finally, the effects of a pan Trk inhibitor, CEP-701 which has been included in some clinical trials for the treatment of PCa. We observed the following: i) TrkA and TrkB expression was significantly higher in AR-negative compared to ARpositive cells; ii) TrkA and TrkB expression was related to the invasive capacity/malignancy of PCa cells; iii) p75 NGFR could be considered a tumor suppressor gene which is present at high levels only in AR-positive cells; and iv) that NGF and BDNF (targeting TrkA/p75 NTR and TrKB, respectively) induced cell migration and this was inhibited by the CEP-701 treatment. In conclusion, the malignancy of PCa seems to be accompanied by increased TrkA and TrkB signaling (with a reduction of p75 NGFR expression) and CEP-701 could be used to reduce the metastasis formation in advanced PCa. CEP-701 is a trademark

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

“…In fact, constitutive activation of TRKs has been detected in several tumor types, including leukemias (45), and a novel alternative splicing variant with constitutive oncogenic potential has been recently described in neuroblastoma (46). Somatic rearrangements of TRKA, producing chimeric oncogenes with constitutive tyrosine kinase activity, have been detected in a consistent fraction of papillary thyroid tumors (18), and an autocrine loop involving TRKA and NGF has been associated with tumor progression in prostate, ovarian, pancreatic, and breast cancer (20)(21)(22)(23)(24).…”

“…Physiologically, the TRK/neurotrophin axis plays a role in neuronal maintenance and survival during development (17). TRK/neurotrophins have, however, also been implicated in cancer: Genetic rearrangement and activation of TRKA, for example, has been found in colon and papillary thyroid cancers (18), and of TRKC in several tumor types (19), whereas autocrine or paracrine activation of TRKs has been implicated in various cancers, including neuroblastoma, mesothelioma, pancreas, prostate, ovarian, and breast carcinomas (20)(21)(22)(23)(24).…”

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

“…No TRKA inhibitors were explored in clinical trials with the possible exception of lestaurtinib (CEP-701), a staurosporine-derivative multikinase inhibitor that was investigated in clinical settings with reported TRKA overexpression, without evidence of efficacy (7,38). However, recent studies that have identified recurring oncogenic NTRK1 rearrangements in subsets of NSCLC and colorectal carcinoma patients (11,12), as well as other studies suggesting a potential role of activated TRKA in other tumor types, including glioblastoma and Spitz melanoma (14)(15)(16)39), have created much renewed interest in the identification and clinical investigation of effective TRKA inhibitors (13).…”

“…Whereas the physiologic role of TRKA is relatively well elucidated (4), its involvement in neoplastic transformation and tumor progression was until very recently limited to identification of rearrangements in papillary thyroid carcinoma (PTC), a tumor type characterized by a relatively good prognosis and reports of activation due to presence of putative autocrine loops in neuroblastoma, prostate, pancreatic, and breast cancer (5)(6)(7)(8)(9)(10). However, chromosomal rearrangements involving the NTRK1 gene, resulting in the expression of different TRKA fusion proteins were recently reported by Vaishnavi and colleagues (11) in NSCLC, along with robust preclinical demonstration of the oncogenic potential of the predicted chimeric proteins.…”

New perspectives on the treatment of differentiated thyroid cancer

“…Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro (54). This drug might be beneficial in the treatment of patients with papillary thyroid cancer with rearrangements of NTRK1, although it has not been tested.…”