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Preprint WatchModerateOctober 15th, 2026

A Multi-Kinase Inhibitor Screen Identifies mTOR Signaling as a Vulnerability in Advanced Prostate Cancer.

Sridhar, S.; Mohan, K.; Kizhake, S.; Natarajan, A.; Kelly, D. L.; Mathew, G.

AXL expression is downregulated rather than gained in aggressive and treatment-resistant prostate cancer, and isogenic AXL knockout cells show selective vulnerability to PI3K, AKT and mTOR pathway inhibition, so mTOR inhibition is proposed as a strategy for AXL-deficient disease.

Moderate contradiction

2 prior failures

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

This preprint inverts the direction of the usual AXL hypothesis. It reports that AXL downregulation, not overexpression, tracks with treatment resistance and shorter survival in prostate cancer, and that AXL loss creates a PI3K, AKT and mTOR dependency. Claidex holds two AXL failures in which the therapeutic premise ran the other way. In sitravatinib-axl-tam-post-checkpoint-nsclc-sapphire-phase3-translational-mismatch a TAM-family inhibitor failed a Phase 3 in post-checkpoint lung cancer, logged as a translational mismatch, and in bemcentinib-axl-lung-adenocarcinoma-phase1b2-supply-termination a selective AXL inhibitor programme ended before an efficacy answer. The preprint concerns a different tumour type, so it does not refute those trials, but it does supply a mechanistic reason why AXL inhibition can disappoint: in some contexts low AXL marks the aggressive state. Any new AXL-directed programme should show that AXL is expressed and functionally required in the enrolled population before dosing. The proposed mTOR alternative carries its own record, since everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination stopped for futility.

Abstract excerpt

The receptor tyrosine kinase AXL has context-dependent roles in prostate cancer (PCa). Although AXL signaling has been implicated in PCa progression, it can also promote disseminated tumor cell dormancy. Paradoxically, AXL expression has been reported to be lost in metastatic PCa. This raises two critical questions: Is AXL loss associated with aggressive disease, and does it create therapeutically exploitable vulnerabilities? In this study, we comprehensively analyzed AXL expression across pan-cancer and PCa cohorts and found that AXL downregulation was significantly associated with treatment resistance, aggressive PCa phenotypes, and shorter overall survival. To investigate the functional consequences of AXL loss, we used CRISPR-Cas9 based gene editing to generate isogenic AXLKO cells and characterized their proliferative and migratory properties. To identify therapeutically exploitable vulnerabilities associated with AXL loss, we screened these cells against a library of 1,814 kinase inhibitors using the isogenic cell lines. We identified Torin-2 as a candidate therapeutic agent and validated its activity using dose-response assays, which demonstrated an ~ 18-fold lower IC50 in AXLKO cells than in AXLWT cells. In parallel, PRISM/DepMap analysis provided orthogonal evidence of drug dependencies associated with low AXL expression and revealed a selective vulnerability of AXLKO cells to PI3K/AKT/mTOR pathway inhibition. Collectively, our findings link AXL downregulation to aggressive PCa phenotypes and identify mTOR inhibition as a potential therapeutic strategy for AXL-deficient PCa.

Matching Claidex post-mortems

2 of 2 indexed

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.