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• W4362555501 abstract "<div>Abstract<p>The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)–deficient, MMR-proficient, <i>RAS</i>-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I <i>MSH6</i> variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the <i>MSH6</i> mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment.</p>Significance:<p>MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments.</p><p><i><a href=https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-22-0492 target=_blank>See related commentary by Willis and Overman, p. 1612</a>.</i></p><p><i><a href=https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-7-ITI target=_blank>This article is highlighted in the In This Issue feature, p. 1599</a></i></p></div>" @default.
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• W4362555501 date "2023-04-04" @default.
• W4362555501 modified "2023-10-14" @default.
• W4362555501 title "Data from Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients" @default.
• W4362555501 doi "https://doi.org/10.1158/2159-8290.c.6549607" @default.
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