Use of dual mTOR inhibitor MLN0128 against everolimus-resistant breast cancer

  • Karineh Petrossian
  • Duc Nguyen
  • Chiao Lo
  • Noriko Kanaya
  • George Somlo
  • Yvonne Xiaoyong Cui
  • Chiun-Sheng Huang
  • Shiuan Chen
Preclinical study
  • 87 Downloads

Abstract

Purpose

HR+/HER2− aromatase inhibitor-resistant metastatic breast cancer can be treated with everolimus and a second AI until the cancer recurs. Targeting these everolimus-resistant patients with the latest standard of care, CDK4/6 inhibitors, has not been clearly addressed. Understanding the signaling transduction pathways, which everolimus resistance activates, will elucidate the mechanisms and offer treatment strategies of everolimus resistance.

Methods

To mimic the clinical setting, letrozole-resistant cells were used to generate an everolimus-resistant model (RAD-R). Reverse phase protein array (RPPA) was performed to reveal changes in the signaling transduction pathways, and expression levels of key proteins were analyzed. Inhibitors targeting the major signaling pathways, a CDK4/6 inhibitor palbociclib and a mTORC1/2 inhibitor (MLN0128), were evaluated to establish resistance mechanisms of RAD-R.

Results

RPPA results from RAD-R indicated changes to significant regulatory pathways and upregulation of p-AKT expression level associating with everolimus resistance. MLN0128, that inhibits the AKT phosphorylation, effectively suppressed the proliferation of RAD-R cells while treatment with palbociclib had no effect.

Conclusion

Among the many signaling transduction pathways, which are altered post everolimus resistance, targeting dual mTORC1/2 is a possible option for patients who have recurrent disease from previous everolimus treatment.

Keywords

MTOR inhibitors MLN0128 Everolimus AI resistance 

Abbreviations

AI

Aromatase inhibitor

HR

Hormone receptor

LET-R

Letrozole-resistant cell line

PFS

Progression-free survival

RAD-R

Everolimus-resistant cell line

RPPA

Reverse phase protein array

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest.

Supplementary material

10549_2018_4779_MOESM1_ESM.ppt (250 kb)
Supplementary material 1 (PPT 248 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Cancer BiologyBeckman Research Institute of the City of HopeDuarteUSA
  2. 2.Department of Breast HealthNational Taiwan University HospitalTaipei CityTaiwan
  3. 3.Department of Medical Oncology and Therapeutics ResearchCity of Hope Medical CenterDuarteUSA

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