Playing cancer at its own game: activating mitogenic signaling as a paradoxical intervention

In psychotherapy, paradoxical interventions are characterized by a deliberate reinforcement of the pathological behavior to improve the clinical condition. Such a counter‐intuitive approach can be considered when more conventional interventions fail. The development of targeted cancer therapies has enabled the selective inhibition of activated oncogenic signaling pathways. However, in advanced cancers, such therapies, on average, deliver modest benefits due to the development of resistance. Here, we review the perspective of a ‘paradoxical intervention’ in cancer therapy: rather than attempting to inhibit oncogenic signaling, the proposed therapy would further activate mitogenic signaling to disrupt the labile homeostasis of cancer cells and overload stress response pathways. Such overactivation can potentially be combined with stress‐targeted drugs to kill overstressed cancer cells. Although counter‐intuitive, such an approach exploits intrinsic and ubiquitous differences between normal and cancer cells. We discuss the background underlying this unconventional approach and how such intervention might address some current challenges in cancer therapy.