Bi-steric mTORC1-selective Inhibitors activate 4EBP1 reversing MYC-induced tumorigenesis and synergize with immunotherapy

We evaluated the therapeutic efficacy and transcriptome changes induced in hepatocellular carcinoma upon treatment of Lap-tTA/Tet-O-MYC transgenic mice with two Bi-steric mTORC1-selective inhibitors, sorafenib, or doxycycline to inactivate MYC via the TET system at different time points post treatment. Lap-tTA/Tet-O-MYC mice were taken off doxycycline to activate the human transgenic MYC oncogene 4 weeks after being born, then after waiting 4-5 weeks, mice were imaged using magnetic resonance imaging (MRI) every week to precisely define tumor volumes before treatment enrollment. Mice bearing HCC tumors with these volumes were assigned to one of the following treatment groups: vehicle control (5/5/90 Transcutol/Solutol HS 15/Water) at 10 mg/kg via I.P., doxycycline at 100 µg/ml in water (MYC Off), RMC-4627 at 10 mg/kg I.P. 1x/wk, RMC-6272 at 10 mg/kg I.P. 1x/wk, or Sorafenib at 30 mg/kg/day O.G. (oral gavage). Seven days after treatment, mice were given a second dose of their respective treatments and they were euthanized at 4, 12, 24, 48 or 72 hours to collect and freeze in dry ice HCC tumor chunks.