Exploiting Non-Oncogene Addiction to Overcoming Drug Resistance in Metastatic Neoplasias

Albrecht Reichle^1*Dennis Christoph Harrer¹Florian Lüke¹Tobias Pukrop¹Lina Ghibelli²Daniel Heudobler¹

• ¹University Medical Center Regensburg, Regensburg, Germany
• ²Universita degli Studi di Roma Tor Vergata Dipartimento di Biologia, Rome, Italy

Acquired genetic aberrations implement new information about how tissue systems should perform (Mueller et al. 2018;Hendrix et al. 2007). Emerging tumor systems integrate oncogene-driven information by coordinating vast networks of non-oncogenes within tumor and heterogeneous adjacent stroma cells, ultimately organizing non-oncogene addiction (NOA)-driven circuitries to ensure the viability and resilience of malignant tissues (Xu et al. Integrated oncogenic-triggered information, promoting NOA genome editing, becomes conceivable in novel tissue structures and functions. However, phenomenology does not reveal how oncogenic input is integrated transcriptionally, particularly with regard to the operation of novel oncogene-driven NOA circuitries that span tumor tissue systems (Yuan et The reproducibility of tumor phenomenology, which facilitates traditional tumor classification, hypothesizes that similar integration of oncogenic data is associated with a distinct input of oncogenic information. However, how is oncogenic information integration formally structured at the non-oncogene level?All five papers focus on the tension between oncogenic information input and comprehensive integration of non-oncogenes. TTE-initiated reprogramming of NOA circuitries may be followed by pivotal responses in r/r hematological malignancies, cancers and sarcomas, as indicated by long-term disease stabilization, objective response, complete remission (CR) or continuous CR. Transcriptionally targeting oncogene-driven data integration plus 'jump starter' may resolve heterogeneous intra-tumor resistance. The data suggests that novelly arising NOA circuitries manage oncogenic transcriptional data integration but cannot yet be comprehensively pinned down (novel paper).According to the therapeutic success of selected TTE protocols in r/r neoplasias, NOA circuitries that provide identical patterns of clinically important receptor-triggered transcriptional targets may be present in (molecular)-genetically heterogeneous neoplasias, and differential patterns in identical tumor histologies. Notably, identical NOA integration programs have been identified across different tumor histologies, suggesting a genomeagnostic NOA accessibility altogether (novel paper).NOA organizations are novel in that they are genome-agnostically supervised by the oncogene-driven transcriptional integration machinery, as shown in 15 clinical trials by the successful receptor-triggered transcriptional accessibility of r/r neoplasias via differential TTE techniques (novel paper) (Harrer et al. 2026). Single NOAs can be pointedly edited, e.g., in r/r Hodgkin's lymphoma for disturbing the NOA-promoted oncogenic data integration with classic targeted therapy, everolimus (Harrer et al. 2025). Among 13 histologically distinct metastatic r/r neoplasias, only in r/r metastatic gastric cancer data integration could not be disrupted through the addition of pioglitazone in a randomized TTE approach.In terms of information, a tumor system creates a distinctive identity by establishing NOAs/NOA circuitries. Thus, the relation between parts and the whole is not simply a claim about a correlation between structures/functions and oncogenic information integration Therefore, TTE designs adapted to oncogenic data integration patterns are directed to specific systems constellations and therefore, characterized by manageable toxicities (novel paper).Due to highly heterogeneous oncogenic events, we participate in an unbelievable number of diverse histologies. However, as indicated clinically, the integration of oncogenic data is manageable in therapeutic terms within the context of systems pharmacology. This is due to the suggested tightly structured transcriptional data integration programs and the multifold developable TTE approaches with repurposed drugs.In contrast to the various, heterogeneous non-synonymous oncogenic events in treated r/r neoplasias, differential TTE techniques reveal that data integration programs are pivotal editable targets, are shared between neoplasias, and genome-agnostic Oncogenic data integration-driven NOA reorganization turned out to be an instrumental target for TTE techniques, representing a novel promising systems pharmacological approach. In the future, diagnosing NOAs, NOA circuitries, oncogenic-integrated receptortriggered transcription factors and editability of NOAs may be as valuable for selecting therapy as histological/molecular genetic tumor typing is for establishing personalized hematology/oncology. The authors D.H., F.L., L.G., and A.R. made substantial contributions to the conception of the All authors approved the submitted paper and agreed to all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. and appropriately documented in the literature. Oncogene-driven in ormation integration in tumor tissues