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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. [ABSTRACT FROM AUTHOR]

In malignant transformation, cellular stress‐response pathways are dynamically mobilized to counterbalance oncogenic activity, keeping cancer cells viable. Therapeutic disruption of this vulnerable homeostasis might change the outcome of many human cancers, particularly those for which no effective therapy is available. Here, we report the use of fibroblast growth factor 2 (FGF2) to demonstrate that further mitogenic activation disrupts cellular homeostasis and strongly sensitizes cancer cells to stress‐targeted therapeutic inhibitors. We show that FGF2 enhanced replication and proteotoxic stresses in a K‐Ras‐driven murine cancer cell model, and combinations of FGF2 and proteasome or DNA damage response‐checkpoint inhibitors triggered cell death. CRISPR/Cas9‐mediated K‐Ras depletion suppressed the malignant phenotype and prevented these synergic toxicities in these murine cells. Moreover, in a panel of human Ewing's sarcoma family tumor cells, sublethal concentrations of bortezomib (proteasome inhibitor) or VE‐821 (ATR inhibitor) induced cell death when combined with FGF2. Sustained MAPK‐ERK1/2 overactivation induced by FGF2 appears to underlie these synthetic lethalities, as late pharmacological inhibition of this pathway restored cell homeostasis and prevented these described synergies. Our results highlight how mitotic signaling pathways which are frequently overridden in malignant transformation might be exploited to disrupt the robustness of cancer cells, ultimately sensitizing them to stress‐targeted therapies. This approach provides a new therapeutic rationale for human cancers, with important implications for tumors still lacking effective treatment, and for those that frequently relapse after treatment with available therapies. We designed an unexplored approach to cancer therapy: mitogenic overstimulation to increase dependence on stress‐response pathways, plus stress‐targeted inhibitors to selectively kill cancer cells. As a proof of principle, we show that exogenous FGF2 enhanced replication and proteotoxic stresses in different cancer cell lines, rendering these cells prone to massive cell death when combined with ATR or proteasome inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Endocytosis is an important regulator of cell–cell signaling and endocytic trafficking has been increasingly implicated in control of tumor suppression. Recent insights from Drosophila indicate that impairment of multiple trafficking steps which lead to receptor degradation can cause tumor formation in epithelial organs. These tumors are characterized by sustained activation of a number of mitogenic signaling pathways, and by subversion of epithelial polarity and the apoptotic response. Cooperation between such alterations, as well as tumor–host interactions, is also observed. The recapitulation of several hallmarks of human cancers in fly tumors provides a framework to understand the role of defective endocytosis in cancer. [Copyright &y& Elsevier]