Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.
Quantitative DNA Repair Biomarkers and Immune Profiling for Temozolomide and Olaparib in Metastatic Colorectal Cancer.
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DOI：
10.1158/2767-9764.crc-23-0045
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发表时间：
2023-06
期刊：
影响因子：
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通讯作者：
Schalper, Kurt A.
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文献类型：
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作者：
Cecchini, Michael;Zhang, Janie Y.;Wei, Wei;Sklar, Jeffrey;Lacy, Jill;Zhong, Minghao;Kong, Yong;Zhao, Hongyu;DiPalermo, Jassim;Devine, Lesley;Stein, Stacey M.;Kortmansky, Jeremy;Johung, Kimberly L.;Bindra, Ranjit S.;LoRusso, Patricia;Schalper, Kurt A.
O 6-甲基鸟嘌呤DNA甲基转移酶（MGMT）沉默的肿瘤显示对替莫唑胺（TMZ）的敏感性，PARP抑制剂可增强这种敏感性。大约40%的结直肠癌具有MGMT沉默，我们的目的是测量TMZ和奥拉帕尼在结直肠癌中的抗肿瘤和免疫调节作用。利用存档肿瘤的甲基化特异性PCR对晚期结直肠癌患者进行MGMT启动子高甲基化筛查。合格患者接受TMZ 75 mg/m2（第1-7天）和奥拉帕尼150 mg每日两次，每21天一次。收集治疗前的肿瘤活检组织进行全外显子组测序（WES）和MGMT蛋白表达和免疫标记物的多重定量免疫荧光（QIF）。 在18/51例（35%）患者中检测到MGMT启动子高甲基化，9例接受研究治疗无客观缓解，5/9例疾病稳定（SD），4/9例疾病进展为最佳缓解。3例患者有临床获益：癌胚抗原降低、放射学肿瘤消退和SD延长。多重QIF的MGMT表达显示6/9例无获益患者的肿瘤MGMT蛋白显著，而3/9例获益患者的MGMT蛋白较低。此外，获益患者的基线CD 8+肿瘤浸润淋巴细胞更高。WES显示8/9例患者存在MAP激酶变体（7例KRAS和1例ERBB 2）。流式细胞术鉴定了效应T细胞的外周扩增。我们的研究结果表明MGMT启动子高甲基化和MGMT蛋白表达之间的不一致性。在MGMT蛋白表达低的患者中观察到的抗肿瘤活性支持MGMT蛋白作为烷化剂敏感性的预测因子。增加的CD 8 + TIL和外周活化T细胞表明免疫刺激组合的作用。TMZ和PARP抑制剂在体外和体内与MGMT沉默的肿瘤中协同作用。高达40%的结直肠癌是MGMT启动子高甲基化的，我们研究了TMZ和奥拉帕尼在这一人群中是否有效。我们还通过QIF测量了MGMT，并仅在低MGMT患者中观察到疗效，表明定量MGMT生物标志物更准确地预测烷化剂组合的获益。
O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1–7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.