Concept 3: Non-oncogene Addiction
Emerging literature suggests an alternative strategy to the multi-target approach. These studies reveal that oncogene activation introduces secondary physiological changes that stress cellular capacity for survival. Consequently, tumour cells becomes more dependent (or hyper-dependent) on processes required to compensate for these stressful conditions. This phenomenon is termed 'non-oncogene addiction' since the compensatory processes required for tumour survival do not directly contribute to the cancer formation. In other words, even the genes that are not themselves targeted by tumorigenic mutations may well become essential for the tumour to survive the stressful environment and fuel the demanding process of tumour progression. Consequently, interfering with the function of such genes could cause tumour kill while sparing the normal counterpart (figure 2).
There are several examples of such critical non-oncogenic pro-survival functions required for the maintenance of the tumorigenic state in glioblastoma. EGFR is a critical proto-oncogene in glioblastoma pathogenesis. Our laboratory has demonstrated that EGFR hyperactivation results in an 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 the DNA repair process required for the repair of ROS-related DNA damage. Selective targeting of EGFR hyperactive glioblastomas can, thus, be achieved by inhibition of these repair processes. Other groups have demonstrated that EGFR hyperactivation in glioblastoma cell lines heightens requirement for lipogenesis. Additional 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 tumour microenvironment including the immune system.
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 biological 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. Targeting genes that are synthetically lethal with oncogenes constitutes an attractive means to this end.
It is important to note that the effects of therapies designed based on the principles of 'oncogene addiction' and 'non-oncogene addiction' are inherently antagonistic. For instance, EGFR inhibition leads to a reduction in ROS, obviating the need for DNA repair. In this context, the combination of DNA repair inhibition and EGFR inhibition would not be desirable. Rational strategies for synthesising the two therapeutic paradigms remains a major intellectual challenge.