Journal Article

TrkA overexpression in non-tumorigenic human breast cell lines confers oncogenic and metastatic properties

Dennison, Lauren, Cravero, Karen, Waters, Ian, Kyker-Snowman, Kelly, Donaldson, Josh, Hunter, Natasha, Park, Ben Ho, Hurley, Paula J., Karthikeyan, Swathi, Konstantopoulos, Konstantinos, Yankaskas, Christopher L., Hughes, Robert M., Christenson, Eric S., Button, Berry, Rosen, David Marc, Croessmann, Sarah

2020

نظرة عامة

Background/purpose TrkA overexpression occurs in over 20% of breast cancers, including triple-negative breast cancers (TNBC), and has recently been recognized as a potential driver of carcinogenesis. Recent clinical trials of pan-Trk inhibitors have demonstrated targeted activity against tumors harboring NTRK fusions, a relatively rare alteration across human cancers. Despite this success, current clinical trials have not investigated TrkA overexpression as an additional therapeutic target for pan-Trk inhibitors. Here, we evaluate the cancerous phenotypes of TrkA overexpression relative to NTRK1 fusions in human cells and assess response to pharmacologic Trk inhibition. Experimental design/methods To evaluate the clinical utility of TrkA overexpression, a panel of TrkA overexpressing cells were developed via stable transfection of an NTRK1 vector into the non-tumorigenic breast cell lines, MCF10A and hTERT-IMEC. A panel of positive controls was generated via stable transfection with a CD74-NTRK1 fusion vector into MCF10A cells. Cells were assessed via various in vitro and in vivo analyses to determine the transformative potential and targetability of TrkA overexpression. Results TrkA overexpressing cells demonstrated transformative phenotypes similar to Trk fusions, indicating increased oncogenic potential. TrkA overexpressing cells demonstrated growth factor-independent proliferation, increased PI3Kinase and MAPKinase pathway activation, anchorage-independent growth, and increased migratory capacity. These phenotypes were abrogated by the addition of the pan-Trk inhibitor, larotrectinib. In vivo analysis demonstrated increased tumorgenicity and metastatic potential of TrkA overexpressing breast cancer cells. Conclusions Herein, we demonstrate TrkA overexpressing cells show increased tumorgenicity and are sensitive to pan-Trk inhibitors. These data suggest that TrkA overexpression may be an additional target for pan-Trk inhibitors and provide a targeted therapy for breast cancer patients.

• الناشر: Springer US,Springer,Springer Nature B.V
• موضوع: Analysis / Breast cancer / Cancer research / Carcinogenesis / Cell fusion / Cell proliferation / Cells / Clinical trials / Health aspects / Medical colleges / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Metastases / Metastasis / Oncology / Phenotypes / Preclinical Study / Telomerase reverse transcriptase / Therapeutic applications / Transfection / TrkA protein / Tumors