**4. Concept 3: Non-oncogene addiction**

Emerging literature suggests an alternative strategy to the multi-target approach. These studies reveal that oncogene activation introduces secondary physiologic changes that stress cellular capacity for survival. Consequently, tumor cells become hyper-dependent on processes required to compensate for these stressful conditions 26, 27. This phenomenon is termed "non-oncogene addiction" since the compensatory processes required for tumor survival do not directly contribute to the cancer formation. In other words, even genes that are not themselves targeted by tumorigenic mutations may well become essential for the tumor to survive the stressful environment and fuel the demanding process of tumor progression. Consequently, interference with the function of such genes can be rate-limiting to the particular mechanism in the tumor, but not as much in the normal counterpart cells. Importantly, such adaptively essential genes that underlie the 'non-oncogene addiction' 26, 27 of cancer cells can be therapeutically targeted if suitable drugs or other approaches are available.

There are several examples of such critical non-oncogenic pro-survival functions required for maintenance of the tumorigenic state in glioblastoma. EGFR is a critical proto-oncogene in glioblastoma pathogenesis 10, 28. Our laboratory has demonstrated that EGFR hyperactivation results in increased accumulation of reactive oxygen species (ROS), which in turn cause cytotoxic DNA damage. To compensate for the deleterious effect of ROS, EGFR hyperactive glioblastomas exhibit increased reliance on DNA repair process that repair ROS related DNA damage 29. Selective targeting of EGFR hyperactive glioblastomas can, thus, be achieved by inhibition of these repair process. Other groups have demonstrated that EGFR hyperactivation in glioblastoma cell lines heightens requirement for lipogenesis 30, 31. Other examples of such critical non-oncogenic pro-survival functions required for maintenance of the tumorigenic state include dependency on mechanism for compensating mitotic and proteotoxic stress and interplay with the tumor microenvironment including the immune system 26. While illustrative examples of strategies based on these "non-oncogene" addiction paradigms have been established in other cancers, the pertinence to glioblastoma awaits rigorous interrogation.

The principle of non-oncogene addiction suggests that there is a wider spectrum of therapeutic options than afforded under the paradigm of "oncogene addiction". In many cases, compensatory processes involved in "non-oncogene addiction" are the same as those that basic scientists have studied for years (for instance, DNA repair). Mechanistic investigations into these biologic processes by the basic scientists have yielded a rich database of inhibitors. Thus, identifying gene functions that compensate for oncogene induced cellular stress should afford opportunities to tap into this rich database and expand the denominator of drugs available for combinatorial therapy. Identifying genes that are synthetically lethal with oncogenes constitute an attractive means to this end.

It is important to note that effects of therapies designed based on the principles of "oncogene addiction" and of "non-oncogene addiction" are inherently antagonistic. For instance, EGFR inhibition leads to a reduction of ROS, obviating the need for DNA repair 29. In this context, combination of DNA repair inhibition and EGFR inhibition would not be desirable. Rational strategies for synthesizing the two therapeutic paradigms remains a major intellectual challenge.
