Breast Cancer Research and Treatment

, Volume 170, Issue 3, pp 499–506 | Cite as

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



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.


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.


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.


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.


MTOR inhibitors MLN0128 Everolimus AI resistance 



Aromatase inhibitor


Hormone receptor


Letrozole-resistant cell line


Progression-free survival


Everolimus-resistant cell line


Reverse phase protein array



This work was supported by the Panda Charitable Foundation and the National Cancer Institute (P30CA033572).

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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