Haratake Naoki, Ozawa Hiroki, Morimoto Yoshihiro, Yamashita Nami, Daimon Tatsuaki, Bhattacharya Atrayee, Wang Keyi, Nakashoji Ayako, Isozaki Hideko, Shimokawa Mototsugu, Kikutake Chie, Suyama Mikita, Hashinokuchi Asato, Takada Kazuki, Takenaka Tomoyoshi, Yoshizumi Tomoharu, Mitsudomi Tetsuya, Hata Aaron N, Kufe Donald
Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts.
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
J Thorac Oncol. 2024 Mar;19(3):434-450. doi: 10.1016/j.jtho.2023.10.017. Epub 2023 Nov 3.
Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance.
H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity.
We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs.
Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.
奥希替尼是一种不可逆的表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，被批准用于一线治疗携带EGFR外显子19缺失或L858R突变的转移性非小细胞肺癌（NSCLC）患者。接受奥希替尼治疗的患者总会通过涉及额外EGFR突变、MET扩增和其他途径的机制产生获得性耐药。目前尚不清楚致癌性MUC1-C蛋白是否参与奥希替尼获得性耐药。
在EGFR通路激活、克隆形成能力和自我更新能力的研究中，对H1975/EGFR（L858R/T790M）细胞和具有奥希替尼获得性耐药的患者来源的NSCLC细胞进行MUC1-C依赖性研究。
我们发现MUC1-C在H1975奥希替尼耐药持久性细胞中上调，并且是EGFR通路激活所必需的。从具有奥希替尼获得性耐药的患者中分离出的、经筛选具有稳定奥希替尼耐药性的H1975细胞（H1975-OR）和MGH700-2D细胞被发现对MUC1-C有依赖性，可诱导（1）磷酸化（p）-EGFR、p-ERK和p-AKT，（2）上皮-间质转化（EMT），以及（3）耐药表型。我们报告，在获得奥希替尼耐药的（1）MET扩增的MGH170-1D #2细胞和（2）MGH121 Res#2/EGFR（T790M/C797S）细胞中，MUC1-C对于p-EGFR、p-ERK和p-AKT激活以及自我更新能力也是必需的。重要的是，在这些不同模型中靶向MUC1-C可逆转奥希替尼耐药。为支持这些结果，高MUC1 mRNA和MUC1-C蛋白表达与EGFR突变的NSCLC患者的不良预后相关。
我们的研究结果表明，MUC1-C是奥希替尼耐药的常见效应因子，并且是治疗奥希替尼耐药NSCLC的潜在靶点。
