Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Department of Population and Public Health Sciences, Keck School of Medicine of USC, Los Angeles, CA.
JCO Precis Oncol. 2023 Jul;7:e2200422. doi: 10.1200/PO.22.00422.
Activating mutations in , , and are known to cause resistance to anti-epidermal growth factor receptor (EGFR) therapy; however, only approximately 40% of patients with colorectal cancer (CRC) with tumors respond to anti-EGFR treatment. We sought to discover novel biomarkers to predict response to anti-EGFR antibody treatment in CRC and to understand mechanisms of resistance to anti-EGFR therapy.
Transcriptomic profiles from three clinical and two preclinical cohorts treated with cetuximab were used to assign consensus molecular subtypes (CMS) to each sample and correlated with outcomes.
Restricting to patients, we observed that CMS2 tumors (canonical subtype) had significantly higher response rates relative to other CMS when treated with cetuximab combination with doublet chemotherapy (Okita et al cohort: 92% disease control rate (DCR) for CMS2, chi-square = .04; CALGB/SWOG 80405 cohort: 90% objective response rate (ORR) for CMS2, chi-square < .001) and with single-agent cetuximab (68%, chi-square = .01). CMS2 tumors showed best response among right-sided (ORR = 80%) and left-sided (ORR = 92%) tumors in the CALGB/SWOG 80405 cohort. CMS2 cells lines were most likely to be sensitive to cetuximab (60%) and CMS2 patient-derived xenograft had the highest DCR (84%). We found Myc, E2F, and mammalian target of rapamycin pathways were consistently upregulated in resistant samples (enrichment score >1, false discovery rate <0.25). Inhibitors of these pathways in resistant cell lines exhibited additive effects with cetuximab.
These data suggest that CRC transcriptional profiles, when used to assign CMS, provide additional ability to predict response to anti-EGFR therapy relative to using tumor sidedness alone. Notably both right-sided and left-sided CMS2 tumors had excellent response, suggesting that anti-EGFR therapy be included as a treatment option for right-sided CMS2 tumors.
已知 、 和 中的激活突变会导致对表皮生长因子受体（EGFR）治疗的耐药性；然而，仅有大约 40%的 肿瘤结直肠癌（CRC）患者对 EGFR 治疗有反应。我们试图发现新的生物标志物来预测 CRC 对 EGFR 抗体治疗的反应，并了解对 EGFR 治疗耐药的机制。
使用来自三个临床和两个临床前队列接受西妥昔单抗治疗的转录组谱将共识分子亚型（CMS）分配给每个样本，并与结果相关联。
限制在 名患者中，我们观察到当用西妥昔单抗联合双药化疗治疗时，CMS2 肿瘤（典型亚型）与其他 CMS 相比，具有更高的反应率（Okita 等人的队列：CMS2 的疾病控制率（DCR）为 92%，卡方=.04；CALGB/SWOG 80405 队列：CMS2 的客观缓解率（ORR）为 90%，卡方<.001）和单药西妥昔单抗（68%，卡方=.01）。在 CALGB/SWOG 80405 队列中，CMS2 肿瘤在右侧（ORR=80%）和左侧（ORR=92%）肿瘤中显示出最佳反应。CMS2 细胞系最有可能对西妥昔单抗敏感（60%），CMS2 患者来源的异种移植具有最高的 DCR（84%）。我们发现 Myc、E2F 和哺乳动物雷帕霉素靶蛋白途径在耐药样本中持续上调（富集评分>1，假发现率<0.25）。在耐药细胞系中，这些途径的抑制剂与西妥昔单抗表现出相加作用。
这些数据表明，CRC 的转录谱用于分配 CMS 时，相对于仅使用肿瘤侧位，提供了额外的预测 EGFR 治疗反应的能力。值得注意的是，右侧和左侧 CMS2 肿瘤均具有极好的反应，这表明抗 EGFR 治疗应作为右侧 CMS2 肿瘤的治疗选择之一。
