Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance

Abstract

A key tool of cancer therapy has been targeted inhibition of oncogene-addicted pathways. However, efficacy has been limited by progressive emergence of resistance as transformed cells adapt. Here, we use to dissect response to targeted therapies. Treatment with a range of kinase inhibitors led to hyperactivation of overall cellular networks, resulting in emergent resistance and expression of stem cell markers, including Sox2. Genetic and drug screens revealed that inhibitors of histone deacetylases, proteasome, and Hsp90 family of proteins restrained this network hyperactivation. These "network brake" cocktails, used as adjuncts, prevented emergent resistance and promoted cell death at subtherapeutic doses. Our results highlight a general response of cells, transformed and normal, to targeted therapies that leads to resistance and toxicity. Pairing targeted therapeutics with subtherapeutic doses of broad-acting "network brake" drugs may provide a means of extending therapeutic utility while reducing whole body toxicity. These findings with a strong therapeutic potential provide an innovative approach of identifying effective combination treatments for cancer. .

Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism

“…To overcome the drug resistance and serious side effects of chemotherapy, a combined treatment approach holds promise for achieving a synergistic anticancer benefit . Das et al …”

“…To overcome the drug resistance and serious side effects of chemotherapy, a combined treatment approach holds promise for achieving a synergistic anticancer benefit. 26 Das et al 27 showed pairing targeted therapeutics with subtherapeutic doses of broad acting "network brake" drugs extended therapeutic utility while reducing whole body toxicity. Since its first discovery, CY has been used as an anticancer drug for more than 40 years in clinical practice, and remains to be a main chemotherapy drug for multiple cancers.…”

Drug screening in Drosophila; why, when, and when not?

“…In a systematic approach to addressing therapy‐induced resistance, Das et al used the above‐described Drosophila RET‐driven tumor model wherein expression of a cancer‐relevant mutant form of Drosophila Ret, dRet MEN2B , in larval epithelial tissues resulted in partial lethality between embryo and pupa stages (Das, Esernio, & Cagan, ). Here, the authors used the Drosophila RET model to ask what OTHER signaling pathways become activated/repressed in response to treatment with a known/approved drug.…”

“…Further, the effect of modulating network components in the normal cells of the larvae can be tested using Drosophila genetics, thus identifying common and unique cellular responses that could explain toxicity and resistance. Once a functionally relevant network has been identified, the authors used known inhibitors to retrain the network to non‐drug levels, so‐called “network breaks,” with the goal of reducing toxicity or resistance (Das et al, ). For example, sorafenib, a poly‐kinase inhibitor approved for the treatment of kidney, liver and thyroid cancers, activated a network that consisted of Erk, Src, and Akt among others.…”

Basic and Translational Models of Cooperative Oncogenesis

“…Finally, Bangi [12] reviews how Drosophila can be utilised to functionally analyse the vast amount of human cancer Omics data that is currently being generated, in order to validate key genes/pathways that contribute to cancer, to build new models to interrogate cancer mechanisms, and to screen for novel cancer therapeutics. Drosophila has already proven its worth in identifying novel drugs that target particular types of human cancers, such as multiple endocrine neoplasia type 2 (MEN2), colorectal and non-small cell lung cancers [36][37][38][39][40][41][42], and undoubtably, the development of more sophisticated Drosophila models that incorporate additional genetic lesions will enable better modelling of human cancers and new anti-cancer drug discovery.…”