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Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib

Bi-Sheng Liu1, Xin-Yu Dai1, Hong-Wei Xia2

  • 1Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.

Molecular Medicine Reports
|August 15, 2018
PubMed

Insights

Combining gefitinib with GGTI-298 overcomes resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. This novel strategy inhibits tumor growth, induces apoptosis, and reduces migration by targeting the EGFR-AKT pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Dysregulation of epidermal growth factor receptor (EGFR) signaling drives resistance to EGFR tyrosine kinase inhibitors (TKIs), leading to tumor progression in non-small cell lung cancer (NSCLC).
  • EGFR TKIs like gefitinib and erlotinib are standard treatments, but acquired resistance remains a significant clinical challenge.

Purpose of the Study:

  • To investigate the efficacy of geranylgeranyl transferase 1 inhibitor (GGTI)-298, alone and in combination with gefitinib, in overcoming EGFR TKI resistance in NSCLC.
  • To elucidate the underlying molecular mechanisms of GGTI-298's anti-cancer effects, particularly its impact on the EGFR-AKT signaling pathway and RhoA activity.

Main Methods:

  • Immunoblotting was used to assess the phosphorylation levels of EGFR and AKT.
  • Cell proliferation was evaluated using combination index (CI) values in NSCLC cell lines (HCC827 and A549).
  • Apoptosis, migration, and Ras homolog family member A (RhoA) activity were measured, with RhoA further investigated using small interfering RNA (siRNA).

Main Results:

  • GGTI-298 inhibited EGFR and AKT phosphorylation, and its combination with gefitinib amplified this inhibition.
  • Synergistic effects on proliferation inhibition (CI <1) were observed when GGTI-298 was combined with gefitinib in NSCLC cell lines.
  • The combination treatment also induced apoptosis and inhibited cell migration, with GGTI-298 found to inhibit RhoA activity, suggesting RhoA mediation in EGFR inhibition.

Conclusions:

  • GGTI-298 demonstrates significant anti-tumor activity in NSCLC, both as a monotherapy and in combination with gefitinib.
  • The combination of gefitinib and GGTI-298 offers a promising therapeutic strategy to overcome EGFR TKI resistance by targeting the EGFR-AKT pathway, potentially via RhoA.
  • Further clinical investigation of this dual-drug approach is warranted for lung cancer treatment.

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