4621 Background: PI3-kinase/ Akt pathway is constitutively activated in pancreatic cancer and is mediated by mTOR kinase. Our in vitro studies suggest that prolonged exposure to mTOR inhibitors can promote insulin receptor substrate-PI3-kinase interactions and paradoxically increase Akt phosphorylation and cyclin D1 expression in pancreatic cancer cells (negative feedback loop). The addition of erlotinib to rapamycin down-regulates rapamycin-stimulated Akt in preclinical models. Methods: Study A: CCI-779 (Temsirolimus), Study B: RAD001 (Everolimus) + Erlotinib. Inclusions: Adult patients with gemcitabine-refractory pancreatic cancer, ECOG PS 0–1, adequate laboratories and measurable disease. Dose and schedule: CCI-779 25 mg IV weekly; RAD001 30 mg weekly + erlotinib 150 mg daily. Primary endpoint: overall survival at 6 months. Secondary endpoints: time-to-progression, response and toxicity. Tumor biopsies analyzed by immunofluorescence and laser scanning cytometry analysis for expression of pmTOR/mTOR, pAkt/Akt, pErk/Erk, pS6, p4EBP-1, PTEN and for k-ras mutations. Results: Study A: 5 patients enrolled, 4 patients received 2–4 doses. 2 patients died within a month; one from rapid progression other from hemorrhagic stroke. 2 developed SAEs: dehydration and asthenia. Study B: 16 patients enrolled; 12 males, all ECOG PS=1. Median cycles=1 (range 1–2). Grade 4 toxicity: hyponatremia (n=1), Grade 3: diarrhea (n=1), cholangitis (n=3), hyperglycemia (n=1), fatigue (n=1). Grade 2: pneumonia (n=2), dehydration (n=2), neutropenia (n=1), mucositis (n=2) & rash (n=2); hospitalizations=4. Progressive disease occurred in 15 and 1 was non-evaluable. Pretreatment biopsies revealed increased pAkt/ Akt ratio in tumor specimens as compared with non malignant pancreatic tissue. No such trends occurred for pErk/Erk or pmTOR/ mTOR. K-ras mutations occurred in 2/7 patient samples. Conclusions: Neither study with mTOR inhibitors demonstrated objective responses or disease stability. Negative feedback loop seen preclinically may account for the rapid progression noted with mTOR inhibitors in pancreatic cancer. The addition of erlotinib may not counter this effect in the clinical setting. [Table: see text]
Autophagy-mediated negative feedback attenuates the oncogenic activity of YAP in pancreatic cancer
