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Preprint WatchModerateJuly 26th, 2026

Occurrence of Biased mTOR Signaling in Hepatocellular Carcinoma

Singh, R.; Patel, N.; Singh, N.; Mourya, P.; Shingade, A.; Mange, A.; Kaur, J.; Beloshe, S.; Dudhalkar, A.; Chavan, P.; Yengkhom, G. D.; Patkar, S.; Goel, M.; Ingle, A.; Tripathy, S. R.; Epari, S.; Arandkar, S.; Thorat, R.; Shetty, S.

mTORC1-S6K-S6 signaling was downregulated in hepatocellular carcinoma while mTORC1-ULK1, mTORC1-4EBP1 and mTORC2-PKC branches were upregulated, and rapamycin-mediated mTORC1 inhibition alone did not reduce tumor progression whereas dual mTORC1/mTORC2 inhibition with Torin 1 did.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that mTOR signaling in hepatocellular carcinoma is branch-biased rather than uniformly hyperactive, with mTORC1-S6K-S6 output reduced and mTORC1-ULK1, mTORC1-4EBP1 and mTORC2-PKC output raised, and that rapamycin failed to slow tumor progression in the model while dual mTORC1 and mTORC2 inhibition with Torin 1 succeeded. The Claidex graph already carries one Phase 2 mTOR efficacy failure, everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination, in which the rapalog everolimus was combined with erlotinib in metastatic pancreatic cancer and the study closed for futility. Everolimus is an mTORC1-selective rapalog, so the branch bias described here is a candidate explanation for why mTORC1-only blockade underperformed in a solid tumor. The finding is preclinical and comes from a carcinogen-induced mouse model plus patient tissue, so it supports a hypothesis rather than settling one. Programs proposing rapalog monotherapy against solid tumors should state which mTOR branch they expect to suppress and show that branch is active in the target indication.

Abstract excerpt

Background: mTOR signaling promotes cell growth and anabolic processes in all eukaryotes. Hyperactivation of mTOR signaling is associated with various cancers along with hepatocellular carcinoma (HCC). HCC is a highly lethal malignancy with multiple aetiologies such as viral infection, alcohol abuse, and metabolic dysfunction. Therapeutic options for HCC remain limited due to an incomplete understanding of oncogenic drivers and poorly characterized mechanisms of disease progression. Methods: Various regimens of DEN and CCl4 carcinogen dosage were investigated on C57BL/6J mice to induce HCC. The histological analysis for fibrosis and serum markers for liver function were performed. Molecular analyses of oncogenic drivers were performed in the HCC tissues obtained from mice and HCC patients. The impact of inhibition of mTOR signaling was assessed on HCC progression. Results: We established a rapid DEN+CCl4 induced (DCI) HCC model in C57BL/6 mice to study disease progression longitudinally. The molecular analysis revealed upregulation of MAPK and downregulation of mTORC1-S6K-S6 signaling in HCC. However, other branches of mTOR such as mTORC1-ULK1, mTORC1-4EBP1, and mTORC2-PKC were upregulated due to the increased expression. Similar observations were found in tissues derived from HCC patients. Furthermore, inhibition of mTORC1 alone by Rapamycin did not reduce HCC progression but Torin 1 mediated inhibition of both mTORC1 and mTORC2 significantly reduced HCC progression. Conclusions: We propose this biased mTOR signaling modulates mTOR activity towards specific downstream processes that are crucial for cancer cell growth and targeting both the mTOR complexes has better therapeutic potential in HCC.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.