RESUMEN
Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in 'N-of-1' cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we sought to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumours with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.
Asunto(s)
Resistencia a Medicamentos/efectos de los fármacos , Resistencia a Medicamentos/genética , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Animales , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Ratones , Mutación/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Inhibidores de Proteínas Quinasas/clasificación , Estructura Terciaria de Proteína/genética , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In 2010, the annual general meeting of the Clinical Investigator Trainee Association of Canada - Association des cliniciens-chercheurs en formation du Canada (CITAC-ACCFC) and the Canadian Society for Clinician Investigators (CSCI) was held between September 20 and 22 in Ottawa. Several globally-renowned scientists, including this year's CSCI/Royal College Henry Friesen Award recipient, Dr. Paul Kubes, Distinguished Scientist Award recipient, Dr. Gideon Koren and Joe Doupe Young Investigator Award recipient, Dr. Torsten Neil, discussed a variety of topics relating to the role of technology in medicine. The meeting was well attended by clinician scientists and trainees from across Canada and offered trainees mentorship and networking opportunities in addition to showcasing their research at the young investigator forum. The aim of this scientific overview is to highlight the research presented by trainees at both the oral plenary session as well as the poster presentation sessions of this meeting. Similar to last year's meeting [1], research questions being investigated by trainees covered the spectrum of medical disciplines, encompassing both basic science as well as clinical areas, and are summarized below.
