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Preprint WatchModerateJuly 28th, 2026

AKT1/mTOR/RICTOR risk variants in Indian hypertrophic cardiomyopathy patients

Chittora, H.; Notani, D.; Dhandapany, P. S.

Rare AKT1, mTOR and RICTOR missense variants identified in Indian hypertrophic cardiomyopathy patients increased mTOR signalling, cell surface area and hypertrophic marker expression in a cardiomyocyte model.

Moderate contradiction

1 prior failure

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

The preprint reports rare AKT1, mTOR and RICTOR missense variants in an Indian hypertrophic cardiomyopathy cohort and shows increased mTOR signalling, larger cell surface area and induction of hypertrophic markers in a cardiomyocyte model. Claidex holds one MTOR failure, everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination, which stopped for futility in metastatic pancreatic cancer. The contrast is instructive rather than contradictory. Where mTOR pathway activation is caused by an identified germline variant, the target inherits genetic support that the oncology combination never had, which is the distinction Claidex records as a genetic deficit. The flag is moderate because the prior failure was an efficacy failure, and the lesson is that indication choice, not the target, carried that result.

Abstract excerpt

Hypertrophic cardiomyopathy is a hereditary heart muscle disease characterized by abnormal ventricular thickening and is predominantly caused by mutations in sarcomeric and signaling genes. Despite these advances, a substantial proportion of patients carry no identifiable pathogenic variants in these genes. Recently, we have shown that mutations in the RPS6KB1 gene (a member of the Akt signaling pathway) can lead to HCM. However, the genetic role of other members of the AKT pathway remains unknown in HCM. To address this gap, we used exome sequencing of an Indian-specific HCM patient cohort and identified six heterozygous missense variants in unrelated patients, including AKT1 (p.G37V), mTOR (p.A152S, p.D297N, p.R1818H), and RICTOR (p.R241Q, p.T1209M). The identified variants were either novel or ultra-rare and were classified as likely pathogenic according to ACMG guidelines. Functional consequences were evaluated using AKT1, mTOR, and RICTOR mutant proteins and compared with wild-type in a cardiomyocyte cell model. All six mutated proteins showed a significant increase in cell surface area, elevated mTOR signaling, induction of hypertrophic marker gene expression, and enhanced global protein synthesis, suggesting a gain-of-function effect. These findings underscore a potential genetic risk associated with the AKT/mTOR/RICTOR axis in patients with HCM.

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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.