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Targeting HSF1 as a Therapeutic Strategy for Multiple Mechanisms of EGFR Inhibitor Resistance in EGFR Mutant

Sangah Lee1,2, Jiyae Jung1,2, Yu-Jin Lee3

  • 1Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 111 Gwahangno, Yuseong-gu, Daejeon 34141, Korea.

Cancers
|July 2, 2021
PubMed

Insights

Heat shock factor 1 (HSF1) is a potential target to overcome acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer. Inhibiting HSF1 triggers apoptosis in resistant cancer cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Non-small-cell lung cancer (NSCLC) treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) often leads to acquired resistance.
  • Multiple receptor tyrosine kinase (RTK) pathways contribute to this resistance, limiting treatment efficacy.
  • Developing strategies to overcome EGFR-TKI resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To identify novel molecular targets for overcoming acquired resistance to EGFR-TKIs in NSCLC.
  • To investigate the role of heat shock factor 1 (HSF1) in mediating resistance to EGFR-TKIs.
  • To evaluate the therapeutic potential of HSF1 inhibition in preclinical models of resistant NSCLC.

Main Methods:

  • Generation of erlotinib-resistant NSCLC cell lines (HCC827-ErlR).
  • Gene expression profiling and Connectivity Map (CMap) analysis to identify potential drug targets.
  • In vitro inhibition of HSF1 using shRNAs and a small molecule inhibitor (KRIBB11).
  • Assessment of downstream protein expression and induction of apoptosis.
  • In vivo efficacy study using a xenograft model of resistant NSCLC.

Main Results:

  • HSF1 was identified as a key target for overcoming EGFR-TKI resistance via CMap analysis.
  • HSF1 inhibition decreased the expression of HSF1 downstream proteins (HSP70, HSP27) and client proteins (BCL2, MCL1, EGFR, MET, AXL).
  • Targeting HSF1 induced apoptosis in EGFR-TKI-resistant cancer cells.
  • HSF1 inhibition demonstrated efficacy in vivo in a preclinical model of resistant NSCLC with mutant EGFR.

Conclusions:

  • The HSF1 signaling pathway, involving HSP90/HSP70/BAG3 and client proteins, represents a viable therapeutic strategy to overcome multiple mechanisms of EGFR-TKI resistance in NSCLC.
  • Targeting HSF1 offers a promising approach to re-sensitize resistant NSCLC tumors to EGFR-TKI therapy.
  • Further clinical investigation of HSF1 inhibitors is warranted for NSCLC patients with acquired resistance.
Keywords:
EGFRHSF1NSCLCinhibitorsresistance

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