Drugging the addict: non-oncogene addiction as a target for cancer therapy

Abstract

Historically, cancers have been treated with chemotherapeutics aimed to have profound effects on tumor cells with only limited effects on normal tissue. This approach was followed by the development of small-molecule inhibitors that can target oncogenic pathways critical for the survival of tumor cells. The clinical targeting of these so-called oncogene addictions, however, is in many instances hampered by the outgrowth of resistant clones. More recently, the proper functioning of non-mutated genes has been shown to enhance the survival of many cancers, a phenomenon called non-oncogene addiction. In the current review, we will focus on the distinct non-oncogenic addictions found in cancer cells, including synthetic lethal interactions, the underlying stress phenotypes, and arising therapeutic opportunities.

Keywords: cancer; non‐oncogene addiction; synthetic lethality; therapy; vulnerability.

Figure 1. Schematic representation of cellular effects of oncogene addiction, synthetic lethality, and non‐oncogene addiction

(A) Oncogene addiction. Cancer cells need continuous oncogenic signaling for their survival. Increased oncogenic signaling in the cancer cell is schematically represented by the arrows. (B) Synthetic lethality. The mutation of individual genes is compatible with cell viability, whereas the combined mutation of these genes leads to cell death. (C) Non‐oncogene addiction. Cancer cells harbor elevated levels of various stresses, caused by collateral events during the tumorigenic process. Tumor cells can be specifically killed by application of additional stress, or by inhibition of specific salvage pathways, whereas normal cells can tolerate these perturbations.