KDM1A inhibition augments the efficacy of rapamycin for the treatment of endometrial cancer

Prabhakar Pitta Venkata, Yihong Chen, Salvador Alejo, Yi He, Bridgitte E. Palacios, Ilanna Loeffel, Junhao Liu, Uday P. Pratap, Gabrielle Gray, Sureshkumar Mulampurath Achuthan Pillai, Yi Zou, Zhao Lai, Takayoshi Suzuki, Suryavathi Viswanadhapalli, Srinath Palakurthi, Rajeshwar R. Tekmal, Ratna K. Vadlamudi, Edward Kost, Gangadhara R. Sareddy

Research output: Contribution to journalArticlepeer-review

Abstract

Endometrial cancer (EC) often exhibit aberrant activation of PI3K/Akt/mTOR signaling and targeted therapies using mTOR inhibitors showed limited success. The epigenetic modifier, lysine-specific histone demethylase-1A (KDM1A/LSD1) is overexpressed in EC, however, the mechanistic and therapeutic implications of KDM1A in EC are poorly understood. Here, using 119 FDA-approved drugs screen, we identified that KDM1A inhibition is highly synergistic with mTOR inhibitors. Combination therapy of KDM1A and mTOR inhibitors potently reduced the cell viability, survival, and migration of EC cells. Mechanistic studies demonstrated that KDM1A inhibition attenuated the activation of mTOR signaling cascade and abolished rapamycin induced feedback activation of Akt. RNA-seq analysis identified that KDM1A inhibition downregulated the expression of genes involved in rapamycin induced activation of Akt, including the mTORC2 complex. Chromatin immunoprecipitation experiments confirmed KDM1A recruitment to the promoter regions of mTORC2 complex genes and that KDM1A inhibition promoted enrichment of repressive H3K9me2 marks at their promoters. Combination therapy of KDM1A inhibitor and rapamycin reduced the tumor growth in EC xenograft and patient derived xenograft models in vivo and patient derived tumor explants ex vivo. Importantly, in silico analysis of TCGA EC patients data sets revealed that KDM1A expression positively correlated with the levels of PI3K/Akt/mTOR genes. Collectively, our results provide compelling evidence that KDM1A inhibition potentiates the activity of mTOR inhibitors by attenuating the feedback activation of Akt survival signaling. Furthermore, the use of concurrent KDM1A and mTOR inhibitors may be an attractive targeted therapy for EC patients.

Original languageEnglish (US)
Pages (from-to)219-231
Number of pages13
JournalCancer Letters
Volume524
DOIs
StatePublished - Jan 1 2022

Keywords

  • Combination therapy
  • Endometrial cancer
  • KDM1A
  • LSD1
  • Rapamycin
  • Sirolimus
  • mTOR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'KDM1A inhibition augments the efficacy of rapamycin for the treatment of endometrial cancer'. Together they form a unique fingerprint.

Cite this