Investigating the therapeutic efficacy of a novel mTORC1 inhibitor, RMC‐6272, on liver tumors with b‐catenin activation

Abstract

Hepatocellular cancers (HCC) are a challenge to treat and lack precision‐based therapies. Gain‐of‐function (GOF) CTNNB1 mutations are evident in around 25‐35% of all HCCs. Co‐expression of mutant CTNNB1 (S45Y) along with proto‐oncogene Met or constitutively active Nrf2, recapitulates 11% and 10% of clinical HCC, respectively. GOF CTNNB1 mutations are also observed in >90% of hepatoblastomas (HBs). Co‐expression of active β‐catenin and Yap in mice leads to the development of HB, representing 80% of all cases. Aberrant activation of the mTOR complex 1 (mTORC1) is observed in both HCC and HB models. In HCC, mutant‐ β‐catenin causes glutamine synthetase‐dependent increase in glutamine, leading to increased S2448‐pmTOR, indicative of mTORC1 activation. In Yap/Ctnnb1 model, mTORC1 activation occurs due to Yap‐regulated increase in glutamine transporter. Here we examine the therapeutic effects of a novel mTORC1 inhibitor RMC‐6272 on the progression of β‐catenin‐driven HCCs and HB. RMC‐6272 belongs to a class of selective mTORC1 inhibitors, termed ‘bi‐steric’, which comprise a rapamycin‐like core moiety covalently linked to an mTOR active‐site inhibitor.MethodsHydrodynamic tail‐vein injection (HDTVI) of S127A‐YAP1 and ΔN90‐CTNNB1 plasmids, together with SB transposase, was used to induce HB development in FVB mice. HCC was induced by co‐expression of S45YCTNNB1 with either Met or G31A‐NFE2L2. Weekly IP administration of RMC‐6272 (Revolution Medicines, 10 mg/kg) was started at 1 week post HDTVI in HB, at 3 weeks in Met‐β‐catenin, and 5 weeks in Nrf2‐β‐catenin models. Animals were euthanized after 7 and 11 weeks of treatment for HB; at 2.5 and 5 weeks for Met‐β‐catenin HCC; and 5 weeks for Nrf2‐ β‐catenin HCC. Liver weight to body weight ratio (LW/BW) was used to address tumor burden. Durability of the RMC‐6272‐elicited response was studied in Yap/β‐catenin and in Nrf2/β‐catenin models by first administering the drug as described above, and then switching to the control treatment for 3 additional weeks, prior to sacrificing them 15 and 13 weeks, respectively, after HDTVI.ResultsTreatment with RMC‐6272 significantly reduced tumor burden in all 3 models. Although both early‐ and late‐end point groups showed some malignant growth, the size and quantity of tumors was diminished by the treatment. The tumor inhibitory effect of RMC‐6272 was more pronounced at late time points by both significantly reduced LW/BW as well as by histology. Moreover, tumor suppressive effects were sustained in both a HB and in a Nrf2‐β‐catenin‐driven HCC, as evident by the significantly reduced LW/BW, even if the treatment had been terminated 3 weeks prior to analysis.ConclusionsOur study demonstrates that RMC‐6272, a novel bi‐steric mTORC1 inhibitor, had a potent multifactorial effect on diminishing HB and HCC growth in relevant murine models. These observations further solidify the potential use of mTORC1 inhibitors as therapeutic agents for CTNNB1‐mutated HCCs and in most HB cases. The bi‐steric mTORC1 inhibitor RMC‐5552 is the first clinical candidate of this class and clinical testing is ongoing (NCT04774952)