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Targeting ROR1 in combination with osimertinib in EGFR mutant lung cancer cells

Nozomu Nakagawa1, Noriko Miyake2, Nobuaki Ochi1

  • 1Department of General Internal Medicine 4, Kawasaki Medical School, 2-6-1 Nakasange, Kita-ku, Okayama, 700-8505, Japan.

Experimental Cell Research
|November 22, 2021
PubMed

Insights

Targeting Receptor tyrosine kinase-like orphan receptor 1 (ROR1) with small interfering RNA (siRNA) combined with osimertinib may overcome EGFR-TKI resistance in lung cancer. This novel combination therapy shows promise for treating EGFR-mutant lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epidermal growth factor receptor (EGFR) mutations drive lung cancer and are targeted by EGFR-tyrosine kinase inhibitors (TKIs) like osimertinib.
  • Resistance to EGFR-TKIs, including osimertinib, remains a significant clinical challenge in EGFR-mutant lung cancer.
  • Receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been implicated as a potential mediator of resistance to targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of ROR1 in osimertinib resistance in EGFR-mutant lung cancer cell lines.
  • To evaluate the efficacy of targeting ROR1 using small interfering RNA (siRNA) in combination with osimertinib.
  • To explore the molecular mechanisms underlying ROR1 inhibition and its impact on cancer cell behavior.

Main Methods:

  • Utilized four lung cancer cell lines with varying sensitivity to osimertinib.
  • Transfected cells with small interfering RNA targeting ROR1 (siROR1) to inhibit its expression.
  • Assessed cell growth, colony formation, apoptosis, and mRNA/protein levels following siROR1 treatment and/or osimertinib exposure.

Main Results:

  • siROR1 treatment significantly suppressed cell growth and colony formation while increasing apoptosis across all tested cell lines.
  • ROR1 inhibition led to reduced mRNA expression of key genes including TGF-β2, AXL, CDH2, PARP1, PEG10, and TYMS.
  • The combination of osimertinib and siROR1 demonstrated enhanced efficacy, particularly in osimertinib-sensitive cell lines, suggesting a synergistic effect.

Conclusions:

  • Targeting ROR1, especially in combination with osimertinib, represents a potential therapeutic strategy to overcome osimertinib resistance in EGFR-mutant lung cancer.
  • Inhibition of ROR1 can modulate multiple signaling pathways and gene expressions involved in cancer progression and drug resistance.
  • This study provides a foundation for developing novel combination therapies for lung cancer patients who develop resistance to EGFR-TKIs.
Keywords:
EGFRLung cancerOsimertinibROR1

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