Abstract Background: Pegargiminase (ADI-PEG20) -based chemotherapy quadrupled the overall survival of patients at 3 years (12% versus 3%) with non-epithelioid (biphasic and sarcomatoid) pleural mesothelioma in the randomized placebo-controlled ATOMIC-Meso phase 2-3 trial (AACR 2023, JAMA Oncol 2024). Here, we report a novel genetic biomarker, namely HFE-related hereditary haemochromatosis as a predictor for durable response to arginine deprivation therapy for cancer using pegargiminase. Methods: We scrutinised the Barts patient cohort which recruited 20. 9% (n=52/249) of patients enrolled on the ATOMIC-Meso study to identify potential pharmacogenomic factors linked to a prolonged therapeutic response. This led to identification of an index patient with the HFE C282Y variant who completed 2 years of pegargiminase. Common HFE variants (C282Y and H63D) were generated in the MSTO mesothelioma cell line using CRISPR/Cas9-mediated mutagenesis, followed by characterisation of mutant and parental controls relating to in vitro drug sensitivity, apoptosis, single/double strand DNA breaks (SSBs/DSBs), performed RNAseq to dissect the mechanism of drug action, and analyzed in vivo tumorigenesis and ADI-PEG20 efficacy using xenograft murine studies. Results: The index patient was homozygous for C282Y and was diagnosed with sarcomatoid mesothelioma during venesection to manage his iron overload. He was enrolled on ATOMIC-Meso and unexpectedly completed 2 years of pegargiminase with a durable partial response. Only one other patient at the same institution completed 2 years of pegargiminase with a durable partial response and was heterozygous for the HFE H63D variant with a biphasic mesothelioma. Bed-to-benchside studies confirmed increased ADI-PEG20 sensitivity in MSTOH63D+/- compared to parental cells using a 3D tumor spheroid model as evidenced by caspase 3 activation, PARP cleavage, higher Annexin V staining and upregulation of SSBs and DSBs. To understand the mechanism of enhanced cytotoxicity to ADI-PEG20 we performed RNA-Seq in MSTOH63D+/- and MSTOWT cells. This identified regulation of AP-1 signalling and suppression of Bcl-2 specifically in ADI-PEG20 treated MSTOH63D+/-cells by 48hrs. Differential modulation of the Bcl-2 family triggering enhanced apoptosis was confirmed in the MSTOH63D+/- compared to MSTOWT cells. Finally, MSTOH63D+/- tumors displayed earlier sensitivity to ADI-PEG20 monotherapy compared to MSTOWT tumor parental controls (14 days vs. 28 days) using murine xenografts. There was no difference in survival between MSTOH63D+/- and MSTOWT tumors, although there was a statistically significant earlier growth advantage for MSTOWT cells. Conclusions: In the Barts ATOMIC-Meso patient cohort, our data reveal mutant HFE as a novel pharmacogenomic biomarker for enhanced sensitivity and prolonged remission to pegargiminase-based chemotherapy for mesothelioma. Further analyses of durable responders to pegargiminase are ongoing with prospective clinical trials planned using HFE as a selection biomarker. Citation Format: Peter Wojciech Szlosarek, George Field, Iuliia Pavlyk, Matthew Young, Michael Allen, Josephine Carpentier, Riyaz Shah, Nick Maskell, David Houghton, Amanda Johnston, John Bomalaski, Louise Jones, Michael Sheaff. Germline HFE mutations predict for durable response to arginine depletion with pegargiminase-based chemotherapy in pleural mesothelioma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT139.
Szlosarek et al. (Fri,) studied this question.