Mechanisms of resistance toT-DM1 in HER2-positive breast cancer

Student thesis: Doctoral thesis

Abstract

HER2-positive breast cancer represents around 15-30% of the breast cancer patients. This breast cancer subtype has poor prognosis, followed by the triple negative subtype, which has the worse. Several drugs are currently approved for HER2-positive breast cancer, such as Trastuzumab, Lapatinib and T-DM1. However, often these patients acquire resistance to these therapies in a period of 1 - 2 years. The main goal of this study is defining mechanisms of resistance to T-DM1. First, I have generated T-DM1 resistant cell lines, and I explored in vitro different possibilities to explain how these cells escape from HER2-target therapy. I obtained T-DM1 resistant cells using a PDX-derived cell line (PDX118) through continuous treatment of increasing doses of T-DM1. These cells were tested of resistance to T-DM1 in the presence of this HER2 target drugs. I have tested whether the levels of HER2 by mRNA and protein, copy number, downstream signaling effectors, cytotoxic part of T-DM1 or differential lysosome activity might justify the differences between parental and resistant cells. No differences in copy number, neither at transcript or total protein levels of HER2 was observed in parental versus resistant cells. However, in two of three T-DM1 resistant cultures, the protein levels at the surface of the resistant cells were significantly lower, although the downstream signaling activity remained similar. A HER2 rescue experiment resulted in a partial recovery of the sensibility. HER2 protein levels at the surface of the tumor cells is the main mechanism of resistance to T-DM1 therapy, and also, abnormal function of lysosomes maybe a reason to escape this treatment.
Date of Award20 Jun 2018
Original languageSpanish
Awarding Institution
  • Universitat Autònoma de Barcelona (UAB)
SupervisorJoaquin Vicente Arribas Lopez (Director), Verónica Rodilla (Director) & Assumpció Bosch (Tutor)

Keywords

  • HER2
  • T-DM1
  • Resistance

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