Modulation of lung cancer cell plasticity and heterogeneity with the restoration of cisplatin sensitivity by neurotensin antibody

Cancer Lett. 2019 Mar 1;444:147-161. doi: 10.1016/j.canlet.2018.12.007. Epub 2018 Dec 21.

Abstract

Overall survival of patients with metastatic non-small cell lung cancer (NSCLC) has significantly improved with platinum-based salt treatments and recently with targeted therapies and immunotherapies. However, treatment failure occurs due to acquired or emerging tumor resistance. We developed a monoclonal antibody against the proform of neurotensin (LF-NTS mAb) that alters the homeostasis of tumors overexpressing NTSR1. Neurotensin is frequently overexpressed along with its high affinity receptor (NTSR1) in tumors from epithelial origins. This ligand/receptor complex contributes to the progression of many tumor types by activation of the cellular effects involved in tumor progression (proliferation, survival, migration, and invasion). We demonstrate that LF-NTS mAb operates on the plasticity of tumor cells overexpressing NTSR1 and lowers their aggressiveness. The mAb enables the restoration of platinum-based therapies responsiveness, while also decreasing metastatic processes. Efficacy dosage with long-term treatment showed no obvious adverse events, while demonstrating improvement in the performance status. Our data suggests that LF-NTS mAb is an ideal candidate to be safely added to the conventional standard of care in order to improve its efficacy.

Keywords: Advanced lung cancer; Anti-tumor drug; Neurotensin antibody; Restoration of platinum salt-based chemotherapy sensitivity; Tumor cell plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / immunology
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Proliferation
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Female
  • Follow-Up Studies
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neurotensin / antagonists & inhibitors*
  • Neurotensin / immunology
  • Neurotensin / metabolism
  • Prognosis
  • Receptors, Neurotensin / antagonists & inhibitors*
  • Receptors, Neurotensin / immunology
  • Receptors, Neurotensin / metabolism
  • Retrospective Studies
  • Survival Rate
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Receptors, Neurotensin
  • neurotensin type 1 receptor
  • Neurotensin
  • Cisplatin