Molecular Pathways: Targeting Hsp90, who benefits and who does not
Cet article passe en revue les perspectives offertes par l'inhibition de la protéine de choc thermique Hsp90 pour le développement de traitements anticancéreux
Many kinase and hormone receptors, important for cancer cell proliferation and survival, bind to and are dependent on Hsp90 cycle for their folding and maturation. This provides the rationale for the development of small molecule ATP competitors that, inhibiting Hsp90 function, lead to degradation of the "client" proteins. After continuous efforts to improve the pharmacological properties and the tolerability of these molecules, several Hsp90 inhibitors have exhibited activity in both preclinical models and in the clinical setting. However, as is the case with many other targeted agents, patient selection seems to be the major limitation to the success of these compounds. ERBB2 positive breast cancer patients are exquisitely sensitive to Hsp90 inhibition. This is because ERBB2 is indispensable for growth and survival of this subtype of cancer, and, at the same time, ERBB2 is a client protein strictly dependent on Hsp90 for its maturation and stability. Extensive preclinical work identifying other ERBB-like client proteins, will likely lead to the ability to enhance selection of appropriate patients for enrollment in more rational clinical trials. Hsp90 inhibition has also been reported to synergize with other therapeutic agents. Several ongoing studies testing different combinations of Hsp90 inhibitors with other targeted agents will confirm whether Hsp90 inhibition can potentiate the efficacy of targeted therapy and/or prevent the emergence of drug resistance.