Non-oncogene dependencies: Novel opportunities for cancer therapy

Targeting oncogene addictions have changed the history of subsets of malignancies and continues to represent an excellent therapeutic opportunity. Nonetheless, alternative strategies are required to treat malignancies driven by undruggable oncogenes or loss of tumor suppressor genes and to overcome drug resistance also occurring in cancers addicted to actionable drivers. The discovery of non-oncogene addiction (NOA) uncovered novel therapeutically exploitable "Achilles' heels". NOA refers to genes/pathways not oncogenic per sé but essential for the tumor cell growth/survival while dispensable for normal cells. The clinical success of several classes of conventional and molecular targeted agents can be ascribed to their impact on both tumor cell-associated intrinsic as well as microenvironment-related extrinsic NOA. The integration of genetic, computational and pharmacological high-throughput approaches led to the identification of an expanded repertoire of synthetic lethality interactions implicating NOA targets. Only a few of them have been translated into the clinics as most NOA vulnerabilities are not easily druggable or appealing targets. Nonetheless, their identification has provided in-depth knowledge of tumor pathobiology and suggested novel therapeutic opportunities. Here, we summarize conceptual framework of intrinsic and extrinsic NOA providing exploitable vulnerabilities. Conventional and emerging methodological approaches used to disclose NOA dependencies are reported together with their limits. We illustrate NOA paradigmatic and peculiar examples and outline the functional/mechanistic aspects, potential druggability and translational interest. Finally, we comment on difficulties in exploiting the NOA-generated knowledge to develop novel therapeutic approaches to be translated into the clinics and to fully harness the potential of clinically available drugs.