---
title: "MGMT Silencing Predicts Response to O6-Fluoroethylation and Sensitizes AML to ATR Inhibition"
id: "biorxiv-5-biomarker-targeted-o6-guanine-alkylation-potentiates-atr-inhibitor-response-in"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-5-biomarker-targeted-o6-guanine-alkylation-potentiates-atr-inhibitor-response-in"
content_type: "clinical_feed_article"
specialty: "Hematology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.19.751270v1?rss=1"
published_at: "2026-09-22T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# MGMT Silencing Predicts Response to O6-Fluoroethylation and Sensitizes AML to ATR Inhibition
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-5-biomarker-targeted-o6-guanine-alkylation-potentiates-atr-inhibitor-response-in
- **Specialty:** [Hematology](https://medichelpline.com/clinical-feed/hematology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.19.751270v1?rss=1)
- **Published At:** 2026-09-22T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Acute myeloid leukemia (AML) lacks biomarker-directed therapies and has high relapse rates, motivating identification of actionable vulnerabilities. - The DNA repair enzyme **MGMT** is epigenetically silenced in a subset of cancers and its silencing predicts temozolomide (TMZ) response in glioblastoma; prior TMZ trials in AML produced modest responses. - The authors profiled MGMT across 23 de novo and 16 relapsed/refractory (R/R) primary AML samples using MGMT mRNA, promoter methylation, and protein expression. - Approximately **25–30%** of AMLs in this cohort showed MGMT silencing, while healthy CD34+ hematopoietic stem and progenitor cells consistently expressed MGMT. - Loss of mismatch repair (MMR) proteins was frequent in the AML cohorts; MMR deficiency is a known resistance mechanism to TMZ in glioblastoma. - CRISPR knockout screens and engineered AML models demonstrated that MMR loss drives both primary and acquired TMZ resistance in **MGMT-silenced** AML. - To bypass MMR-dependent resistance, the investigators evaluated MGMT-dependent alkylating agents and identified a fluoroethylating TMZ analog, **KL50 (N3-(2-fluoroethyl) imidazotetrazine)**, with selective activity in MGMT-silenced AML. - KL50 retained antileukemic activity regardless of MMR status and significantly prolonged survival in humanized MISTRG6 mice bearing primary AML patient-derived xenografts. - Mechanistically, KL50 produced time-dependent formation of **interstrand DNA crosslinks**, induced DNA damage, and triggered a replication stress response dominated by **ATR** signaling. - Pharmacologic ATR inhibition synergized with KL50, generating marked antileukemic activity and significantly extending survival across AML models without compromising hematologic safety in the reported experiments. - The study positions **MGMT silencing** as a prevalent, actionable biomarker in AML, highlights **MMR deficiency** as a key determinant of TMZ resistance but not KL50 sensitivity, and supports combining low-dose O6-fluoroethylating agents with ATR inhibitors for de novo and R/R AML across varied genetic backgrounds. - Details on dosing regimens, specific ATR inhibitors used, and full experimental protocols were not reported in the abstract and would require consulting the full preprint for implementation details.
## Clinical Analysis & Structured Key Points
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Sundaram, Sam Friedman, James Elia, Jennifer VanOudenhove, Collin Heer, Ahmad Kiwan, Martin Matthews, Susan Gueble, [ View ORCID Profile](http://orcid.org/0000-0002-2737-9810)Stephanie Halene, [ View ORCID Profile](http://orcid.org/0000-0002-3255-0467)Ranjit Bindra doi: https://doi.org/10.64898/2026.09.19.751270 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. Prateek Bhardwaj 1 YALE UNIVERSITY; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Prateek%2BBhardwaj%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Bhardwaj%20P&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3APrateek%2BBhardwaj%2B) * [ORCID record for Prateek Bhardwaj](http://orcid.org/0000-0001-5546-7829 "Open in new tab") * For correspondence: prateekbhardwaj26@gmail.com Amro Baassiri 2 Yale University * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Amro%2BBaassiri%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Baassiri%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAmro%2BBaassiri%2B) Ranjini K. 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Bindra](http://orcid.org/0000-0002-3255-0467 "Open in new tab") * [Abstract](https://www.biorxiv.org/content/10.64898/2026.09.19.751270v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5800066/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.09.19.751270v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5800066/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.09.19.751270v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5800066/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.09.19.751270v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5800066/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract Acute myeloid leukemia (AML) remains limited by high relapse rates and a scarcity of biomarker-directed therapies, underscoring the need to identify actionable vulnerabilities and mechanisms of therapeutic resistance. O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that directly reverses mutagenic O6-alkylguanine lesions, is epigenetically silenced in multiple cancers. Although MGMT silencing is predictive of temozolomide (TMZ) response in glioblastoma with significant survival advantage, prior clinical trials of TMZ in AML have shown only modest responses. Therefore, the prevalence and therapeutic relevance of MGMT silencing, as well as genetic factors that modify its therapeutic response in AML, remain to be comprehensively investigated. Here, we first profiled MGMT status across a diverse cohort of 23 de novo and 16 relapsed/refractory (R/R) primary AMLs using an integrated analysis of MGMT mRNA expression, promoter methylation, and protein expression. We found that approximately 25-30% of AMLs harbor MGMT silencing, in contrast to consistent MGMT expression in healthy CD34+ hematopoietic stem and progenitor cells. We further identified frequent loss of mismatch repair (MMR) proteins in these AML cohorts, a known resistance mechanism against TMZ in glioblastoma. Using CRISPR knockout screening and genetically engineered AML models, we found that MMR loss also drives both upfront and acquired TMZ resistance in MGMT-silenced AML. These findings identify MMR deficiency as an important and previously underappreciated genetic contributor to the modest responses observed in prior trials of TMZ in AML. To therapeutically exploit MGMT silencing while bypassing genetic determinants of resistance, including MMR deficiency, we evaluated clinically and preclinically characterized MGMT-dependent DNA-alkylating agents and identified a fluoroethylating analog of TMZ, N3-(2-fluoroethyl) imidazotetrazine (KL50), with pronounced and selective activity in MGMT-silenced AML. KL50 retained antileukemic activity irrespective of MMR status, significantly prolonging survival in humanized MISTRG6 mice harboring primary AML patient-derived xenografts. Mechanistically, KL50 induced DNA damage through the time-dependent formation of interstrand DNA crosslinks, bypassing MMR dependence and triggering a replication stress response dominated by ATR signaling. Pharmacologic ATR inhibition synergized with KL50, producing marked antileukemic activity and significantly extending survival across AML models without compromising hematologic safety. Together, these findings establish MGMT silencing as a prevalent and therapeutically actionable biomarker in AML, define MMR status as a key determinant of TMZ response in AML but not KL50 sensitivity, and provide a translational rationale for combining low-dose O6-fluoroethylating imidazotetrazines with ATR inhibitors to target both de novo and R/R AML across diverse genetic backgrounds. ### Competing Interest Statement The authors have no competing interests to disclose. S.E.G. and R.S.B. report licensed intellectual property related to this work, with royalties paid from Yale University, Merck & Co., and Modifi Biosciences. ## Funder Information Declared NIH/NCI, R01CA266604, R01CA222518, R01CA253981 NIH/NIDDK, R01DK124788-01A Edward P. Evans Foundation, https://ror.org/03h22gm35 Frederick A. DeLuca Foundation Yale Cancer Center, https://ror.org/03j7sze86, Leslie Warner Fellowship Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The Universi
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