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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Osalmid inhibits lung adenocarcinoma progression and enhances EGFR-TKI responses: a preclinical and translational
Leilei Wu1,2, Zhijian Xu3, Wenmei Jiang2
1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Background:
Therapeutic resistance to current treatment strategies indicates the need for more effective agents to treat lung adenocarcinoma (LUAD). RRM2 dysregulation has been implicated in LUAD progression and therapeutic resistance. However, whether pharmacological inhibition of ribonucleotide reductase regulatory subunit M2 (RRM2) by osalmid may suppress LUAD growth and enhance epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) responses remains unclear. We sought to explore the antitumor effects of osalmid and investigate potential combinatorial approaches with third-generation EGFR-TKIs to treat LUAD patients with EGFR mutations.
Methods:
Patient data were used to analyze survival based on RRM2 expression. In vitro and in vivo experiments explored the antitumor effects of AZD9291 (Osimertinib), osalmid, and AST2818 (Alflutinib) as single agents and in combination. The combination index (CI) was conducted to assess the synergy effect of two drugs. Ferroptosis-related data obtained via CRISPR screens and western blotting were used to explore the relationships between RRM2 and ferroptosis suppressor genes (GPX4 and SLC7A11). Immunohistochemical analysis of 4-hydroxynonenal (4-HNE) was conducted to evaluate lipid peroxidation in tumor tissues after treatment with osalmid.
Results:
Patients with high RRM2 expression had poorer survival than patients with low RRM2 expression (P<0.001). RRM2 knockdown or osalmid treatment decreased the proliferation and colony formation of LUAD cell lines. When AST2818 and osalmid were combined, the half-maximal inhibitory concentration (IC50) values of AST2818 and AZD9291 were significantly decreased. CI values of AST2818 and osalmid ranged 0.22 to 0.82. EGFR-TKI exposure reduced RRM2 expression, although partial RRM2 rebound was observed under prolonged AST2818 treatment, suggesting potential adaptive regulation. In vivo, AST2818 plus osalmid achieved a higher tumor-suppression rate than AST2818 monotherapy in NCI-H1975 xenografts (89% vs. 70%, P<0.001).
Conclusions:
Our findings suggest that osalmid exerts antitumor activity in LUAD and may enhance EGFR-TKI responses, particularly in EGFR-mutant or RRM2-dependent contexts. Further validation in biomarker-selected models is warranted.
Insights
Osalmid shows antitumor activity in lung adenocarcinoma (LUAD) and enhances epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) efficacy, especially in EGFR-mutant or RRM2-dependent LUAD. This suggests osalmid as a potential therapeutic agent for LUAD.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung adenocarcinoma (LUAD) exhibits therapeutic resistance, necessitating novel treatment strategies.
- Ribonucleotide reductase regulatory subunit M2 (RRM2) dysregulation is linked to LUAD progression and resistance.
- The efficacy of osalmid, a pharmacological inhibitor of RRM2, in suppressing LUAD and enhancing EGFR-TKI responses requires investigation.
Purpose of the Study:
- To explore the antitumor effects of osalmid in LUAD.
- To investigate the potential of osalmid in combination with third-generation EGFR-TKIs for treating LUAD patients with EGFR mutations.
Main Methods:
- Survival analysis based on RRM2 expression in patient data.
- In vitro and in vivo experiments evaluating single-agent and combination therapies (AZD9291, osalmid, AST2818).
- Combination index (CI) analysis for synergy, ferroptosis-related gene analysis (GPX4, SLC7A11), and immunohistochemical analysis of 4-HNE for lipid peroxidation.
Main Results:
- High RRM2 expression correlated with poorer LUAD patient survival (P<0.001).
- Osalmid treatment or RRM2 knockdown reduced LUAD cell proliferation and colony formation.
- Combination of AST2818 and osalmid significantly decreased IC50 values for AST2818 and AZD9291, demonstrating synergy (CI values 0.22-0.82).
- In vivo studies showed superior tumor suppression with AST2818 plus osalmid compared to AST2818 monotherapy (89% vs. 70%, P<0.001).
Conclusions:
- Osalmid exhibits antitumor activity in LUAD.
- Osalmid can enhance EGFR-TKI responses, particularly in EGFR-mutant or RRM2-dependent LUAD.
- Further validation in biomarker-selected models is warranted for clinical application.
