RESUMO
STING (stimulator of interferon genes) activation has considerable potential as a new strategy for cancer therapy, but clinical results have not been encouraging. Recent studies by Hong et al. and Li et al. explain why STING agonists often fail to regress human tumors and propose combinatorial strategies to overcome the protumor effects of STING activation.
Assuntos
Neoplasias , Transdução de Sinais , Humanos , Nucleotidiltransferases/metabolismo , Neoplasias/tratamento farmacológicoRESUMO
A common outcome of androgen deprivation in prostate cancer therapy is disease relapse and progression to castration-resistant prostate cancer (CRPC) via multiple mechanisms. To gain insight into the recent clinical findings that highlighted genomic alterations leading to hyperactivation of PI3K, we examined the roles of the commonly expressed p110 catalytic isoforms of PI3K in a murine model of Pten-null invasive CRPC. While blocking p110α had negligible effects in the development of Pten-null invasive CRPC, either genetic or pharmacologic perturbation of p110ß dramatically slowed CRPC initiation and progression. Once fully established, CRPC tumors became partially resistant to p110ß inhibition, indicating the acquisition of new dependencies. Driven by our genomic analyses highlighting potential roles for the p110ß/RAC/PAK1 and ß-catenin pathways in CRPC, we found that combining p110ß with RAC/PAK1 or tankyrase inhibitors significantly reduced the growth of murine and human CRPC organoids in vitro and in vivo. Because p110ß activity is dispensable for most physiologic processes, our studies support novel therapeutic strategies both for preventing disease progression into CRPC and for treating CRPC. IMPLICATIONS: This work establishes p110ß as a promising target for preventing the progression of primary PTEN-deficient prostate tumors to CRPC, and for treating established CRPC in combination with RAC/PAK1 or tankyrase inhibitors.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Tanquirases , Antagonistas de Androgênios , Animais , Humanos , Masculino , Camundongos , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases , Próstata , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genéticaRESUMO
Cyclin-dependent kinase 7 (CDK7) is implicated in regulating the expression of cancer-dependent genes, and multiple CDK7-targeted therapies are currently under clinical investigation. Three recent studies elucidate the structure of human transcription machinery, offering vital mechanistic insights into CDK7 function and a potential pharmacodynamic marker of CDK7 activity in tumors.
