(526.1) Investigating the therapeutic efficacy of a novel mTORC1 inhibitor, RMC-6272, on liver tumors with b-catenin activation

Poster Board Number: D18
Introduction:

Yekaterina Krutsenko (University of Pittsburgh), Junyan Tao (University of Pittsburgh), Mallika Singh (Revolution Medicines, Inc.), Satdarshan Monga (University of Pittsburgh)

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 gt;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.

Methods: Hydrodynamic 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.

Results: Treatment 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.

Conclusions: Our 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)

Funded in part by grant from Revolution Medicines, 5R01CA251155 and 1R01CA250227