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Runx3 Restoration Regresses K-Ras-Activated Mouse Lung Cancers and Inhibits Recurrence
Ja-Yeol Lee1, Jung-Won Lee1, Tae-Geun Park1
1Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 28644, Republic of Korea.
Abstract:
Oncogenic K-RAS mutations occur in approximately 25% of human lung cancers and are most frequently found in codon 12 (G12C, G12V, and G12D). Mutated K-RAS inhibitors have shown beneficial results in many patients; however, the inhibitors specifically target K-RAS and acquired resistance is a common occurrence. Therefore, new treatments targeting all kinds of oncogenic K-RAS mutations with a durable response are needed. RUNX3 acts as a pioneer factor of the restriction (R)-point, which is critical for the life and death of cells. RUNX3 is inactivated in most K-RAS-activated mouse and human lung cancers. Deletion of mouse lung Runx3 induces adenomas (ADs) and facilitates the development of K-Ras-activated adenocarcinomas (ADCs). In this study, conditional restoration of Runx3 in an established K-Ras-activated mouse lung cancer model regressed both ADs and ADCs and suppressed cancer recurrence, markedly increasing mouse survival. Runx3 restoration suppressed K-Ras-activated lung cancer mainly through Arf-p53 pathway-mediated apoptosis and partly through p53-independent inhibition of proliferation. This study provides in vivo evidence supporting RUNX3 as a therapeutic tool for the treatment of K-RAS-activated lung cancers with a durable response.
Insights
Restoring RUNX3 in K-RAS-activated lung cancer models suppressed tumor growth and recurrence. This suggests RUNX3 is a promising therapeutic target for durable treatment of K-RAS-driven lung cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Oncogenic K-RAS mutations drive approximately 25% of human lung cancers, primarily at codon 12.
- Current K-RAS inhibitors target specific mutations but often lead to acquired resistance.
- RUNX3, a critical cell fate regulator, is frequently inactivated in K-RAS-activated lung cancers.
Purpose of the Study:
- To investigate the therapeutic potential of RUNX3 restoration in K-RAS-activated lung cancer.
- To determine the mechanisms by which RUNX3 impacts tumor progression and recurrence.
Main Methods:
- Utilized a K-RAS-activated mouse lung cancer model.
- Conducted conditional restoration of Runx3 in established tumors.
- Analyzed tumor regression, recurrence, survival rates, and molecular pathways (Arf-p53).
Main Results:
- Conditional Runx3 restoration significantly regressed both adenomas and adenocarcinomas.
- Runx3 restoration suppressed cancer recurrence and markedly increased mouse survival.
- Tumor suppression was mediated by Arf-p53 pathway-induced apoptosis and p53-independent proliferation inhibition.
Conclusions:
- RUNX3 acts as a tumor suppressor in K-RAS-activated lung cancer.
- Restoration of RUNX3 demonstrates significant therapeutic potential for durable treatment of K-RAS-driven lung cancers.
- RUNX3 represents a viable therapeutic target for overcoming resistance to current K-RAS therapies.
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