Therapeutically exploiting primary or therapeutically established non-oncogene addiction

A huge number of drugs targeting oncogenes have been FDA approved and are successfully used, such as immune checkpoint inhibitors, tyrosine kinase inhibitors, anti-angiogenic drugs, etc. Nevertheless, metastatic spread, cancer repopulation and acquired cancer cell resistance, termed M-CRAC, arising in relapsed or refractory tumor disease following pulsed systemic therapies, remains a major obstacle for achieving complete remission (CR) or continuous complete remission (cCR). For addressing these major therapeutic problems, it is necessary to therapeutically draw on genes that are aberrantly expressed in response to oncogenic mutations and often not directly druggable, but essentially required for maintaining tumor integrity, tumor-specific stress responses, and tumor survival. These non-oncogene addicted genes are communicatively interconnected in tumor-specific networks. Thus, combined targeting of primarily available non-oncogene addictions or those therapeutically induced, provides novel patterns of targets for efficacious treatment of metastatic tumors without driver mutations and neoplasias in the relapsed or refractory stage.

In order to therapeutically exploit primary or therapeutically establish non-oncogene addiction, the following approaches are available

- Exploring the therapeutic context for synthetic lethal by targeting non-oncogene addiction: Synthetic lethality provides a conceptual framework for addressing poor drugability, genetic and molecular-genetic tumor heterogeneity, drug resistance, and metastatic tumor disease.

- Targeting therapeutic stress sensitivity of tumors and oncogene addiction: Survival of tumor tissues is promoted by tumor-specific stress responses compared to normal tissues. Mechanisms supporting tumor-specific stress responses may be therapeutically overloaded or sensitized by systems therapeutic approaches, leading to tumor cell death.

- Assessing non-oncogene addiction at different metastatic sites: Are there side-specific differential activity profiles of drug combinations targeting non-oncogene addiction, or is it possible to therapeutically establish prerequisites in metastatic tumor tissue, e.g., with tumor tissue editing techniques, to facilitate induction of CR or cCR by targeting 'edited' non-oncogene addiction?

- Exploring atherapeutic window to establish non-oncogene addiction: Is there a therapeutic window to facilitate with less toxicity non-oncogene addiction and synthetic lethality?

- Induction of non-oncogene addiction for attenuating or resolving metastatic spread, cancer repopulation and acquired cancer cell resistance, termed M-CRAC, particularly in relapsed or refractory tumor disease: M-CRAC is a frequently observed phenomenon following any kind of pulsed therapy and a significant obstacle for achieving cure in metastatic tumor disease.

This Research Topic welcomes original research and review articles focusing on, but not limited to, the following topics: - studies on diagnostics of oncogene addiction, and interaction of oncogenic events and non-oncogene addiction across different tumor types,

- combination therapies targeting non-oncogene addiction,

- in vitro studies or clinical trials therapeutically establishing non-oncogene addiction in tumors without driver mutations,

- The induction of non- oncogene addiction in relapsed or refractory neoplasias.