The phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway is frequently deregulated in
pancreatic cancers, and is believed to be an important determinant of their
biological aggression and drug resistance.
NVP-BEZ235 is a novel, dual class I PI3K/
mammalian target of rapamycin (mTor) inhibitor undergoing phase I human clinical trials. To simulate clinical testing, the effects of
NVP-BEZ235 were studied in five early passage primary
pancreatic cancer xenografts, grown orthotopically. These tumours showed activated PKB/Akt, and increased levels of at least one of the
receptor tyrosine kinases that are commonly activated in
pancreatic cancers. Pharmacodynamic effects were measured following acute single doses, and anticancer effects were determined in separate groups following chronic
drug exposure. Acute oral dosing with
NVP-BEZ235 strongly suppressed the phosphorylation of PKB/Akt, followed by recovery over 24 h. There was also inhibition of Ser235/236 S6
ribosomal protein and Thr37/46 4E-BP1, consistent with the effects of
NVP-BEZ235 as a dual PI3K/mTor inhibitor. Chronic dosing with 45 mg kg(-1) of
NVP-BEZ235 was well tolerated, and produced significant tumour growth inhibition in three models. These results predict that agents targeting the PI3K/Akt/mTor pathway might have anticancer activity in
pancreatic cancer patients, and support the testing of combination studies involving
chemotherapy or other molecular targeted agents.