RUNX3 (Runt-related transcription factor 3, tumor suppressor gene)

Class

Gene therapy — recombinant AAV2 vector encoding RUNX3 (rAAV2-RUNX3), intratumoral administration

Pathway

Restoration of RUNX3 tumor-suppressor expression in the tumor microenvironment; developed for KRAS-mutant NSCLC

RUNX3 (Runt-related transcription factor 3) is a transcription factor that normally acts as a tumor suppressor by regulating genes involved in cell cycle control, apoptosis (programmed cell death), and cellular responses to growth-inhibitory signals such as those carried by the TGF-beta pathway. In many cancers, including lung adenocarcinoma, the gene encoding RUNX3 is silenced—often through chemical modification of its promoter region (DNA methylation) or mislocalization of the protein outside the nucleus—removing a natural brake on tumor growth. This is particularly relevant in tumors driven by mutant KRAS, an oncogene that promotes continuous growth signaling; loss of RUNX3 appears to cooperate with KRAS mutations to accelerate tumor progression and can contribute to resistance against other treatments. The therapeutic rationale is to restore RUNX3 function directly within the tumor rather than to inhibit a driver pathway, using a gene therapy approach: a recombinant adeno-associated viral vector (AAV2) carrying the RUNX3 gene is injected directly into the tumor, delivering new copies of the gene to tumor cells so they can produce functional protein. This strategy addresses a genetic loss-of-function defect rather than blocking an overactive protein, offering an approach distinct from conventional kinase inhibitors used in KRAS-mutant lung cancer.