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Activated estrogen receptor-mitogen-activated protein kinases cross talk confer acquired resistance to lapatinib

Zhe Li1, Sheng-Sheng Yang2, Pei-Hao Yin3

  • 1Department of Thyroid and Breast Surgery, The Tenth People's Hospital of Shanghai, Tongji University Shanghai, China.

Thoracic Cancer
|November 12, 2015
PubMed
Abstract

Insights

Estrogen receptor (ER) signaling activation contributes to acquired resistance to lapatinib in breast cancer. Combining lapatinib with an ER inhibitor, fulvestrant, suppressed resistant cell viability.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Lapatinib efficacy in breast cancer is limited by acquired resistance.
  • Estrogen receptor (ER) signaling may play a compensatory role in resistance development.
  • Investigating ER signaling in lapatinib-resistant BT474 cells is crucial.

Purpose of the Study:

  • To investigate the role of ER signaling compensatory activation in acquired resistance to lapatinib.
  • To elucidate the underlying mechanisms of lapatinib resistance in breast cancer cells.
  • To explore therapeutic strategies combining lapatinib with ER inhibitors.

Main Methods:

  • Generated a lapatinib-resistant BT474 cell model (rBT474).
  • Utilized real-time PCR and Western blotting to analyze HER2 and ER pathways.
  • Assessed cell proliferation using MTT and colony formation assays with lapatinib and/or fulvestrant.

Main Results:

  • rBT474 cells exhibited resistance to lapatinib, with reduced apoptosis.
  • Resistant cells showed PI3K/AKT pathway inhibition and MAPK/ER pathway activation.
  • Src phosphorylation and caveolin-1 expression were upregulated in resistant cells.
  • Lapatinib combined with fulvestrant significantly suppressed rBT474 viability in vitro and in vivo.

Conclusions:

  • Compensatory ER signaling activation contributes to lapatinib resistance in HER2-overexpressing/ERα-positive breast cancer.
  • This resistance mechanism involves PI3K/AKT inhibition and MAPK pathway activation.
  • Targeting ER signaling with fulvestrant may overcome lapatinib resistance.
Keywords:
Acquired resistanceERHER2Lapatinibbreast cancer

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