Abstract 3051: Enhancing matchmaking in targeted therapy (TT) for cancer (ca): Beyond the ‘arranged’ criteria

Abstract Cancer is a unique cellular condition marked by constant activation of oncogenes. Heritable DNA changes (mutations, translocations and copy number alterations) can produce this ‘constant’ state. Theoretically, however, static changes are not limited to DNA alterations in the gene body, but can result from DNA amplification of oncogene's transcription factors (TF) or ligands (for receptor Oncogenes), at a minimum. Constant activation depends on identifying clonal events in oncogenes, but may be also inferred from functional activation of oncogenic pathways in multiple sites of a biopsy as a maneuver to identify the pivotal cancer driver for therapeutic targeting. Targeted therapies have produced major therapeutic benefits especially when drugging pivotal oncogenes. Accordingly, efforts to identify such targets are rational, justifiable and desirable. Standard oncology practice includes next generation sequencing (NGS) for this very purpose. NGS criteria are almost entirely based on DNA variance in the gene body of an expanded lists of cancer genes. NGS, as reported in the literature, identifies targets only in 25% of cases sequenced. We hypothesized that extending DNA criteria to assess TF/Ligand amplification of an extended set of oncogenes will identify rational, but hitherto unrecognized targets increasing the ability to match tumors with relevant Targeted Therapies. Methods: We examined 1,731 tumor samples in The Cancer Genome Atlas agnostic to histology or stage using an extensive list of wild-type (WT) but over-expressed (2 fold) proto-oncogenes. We recorded amplification of canonical TFs, or ligands (for receptor oncogenes). We also assessed the transcriptional activity of the oncogenes examined. The genes identified are used routinely in a major commercial vendor for NGS. Results: 31.7% of cases show gene amplification of ligands or TFs of the list of wild type Oncogenes; 4.7% harbor TF/ligand mutations. ∼60%of cases demonstrate activation of an oncogenic signaling pathways (without DNA changes) despite wild type oncogenes reflected by transcriptional activity at z-score >2. Conclusions: Our method outperforms NGS identifying ‘targets’ to pair tumors with effective Therapies. Many druggable oncogenes are potential targets in unexpected histologies (e.g., Abl in breast cancer). Our method should be integrated in future diagnostic interrogation of cancers. Additionally, the algorithms should change to ‘call’ these TFs and ligands events as ‘actionable’. In doing so, we will be extending beyond the classic oncogene-specific NGS. Assessment of translocations and extrachromosomal DNA mechanisms (among many other proposals) may provide further answers for the remaining cases that cannot be classified using the above. This would allow oncologists to introduce Targeted Therapies to a many patients who currently won’t receive such effective and desperately needed treatments. Citation Format: Farah Mazahreh, Liyan Mazahreh, Ahmad Mazin Safar. Enhancing matchmaking in targeted therapy (TT) for cancer (ca): Beyond the ‘arranged’ criteria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3051.