EGFR单抗西妥昔单抗是临床用于治疗全RAS野生型转移性结直肠癌的一线用药，然而患者常发生获得性耐药致病情进展。目前耐药机制研究大多集中在基因学水平改变，表观遗传学机制不明。课题组前期发现miR-302a在西妥昔单抗耐药细胞株中表达降低,其能促进细胞对西妥昔单抗敏感性,且表达可能受GATA6调控,转录因子NFIB可能是其直接作用靶分子。本研究拟:1.进一步阐明miR-302a在CRC中的表达和其调控西妥昔单抗敏感性的功能;2.阐明GATA6转录调控miR-302a表达并介导西妥昔单抗敏感性;3.研究miR-302a通过抑制靶分子NFIB调控西妥昔单抗敏感性的下游分子调控网络;4. PDX小鼠、类器官培养模型及临床耐药前后标本验证GATA6/miR-302a/NFIB的表达模式和临床潜在治疗价值。本研究有望为理解西妥昔单抗耐药提供表观遗传学新机制，为逆转耐药提供新的靶点和治疗策略。

EGFR monoclonal antibody cetuximab is a first-line therapy for RAS wild-type metastatic colorectal cancer. However, patients often develop acquired resistance, leading to disease progression. At present, most studies on drug resistance mechanisms focus on genetic alterations, and the epigenetic mechanism is largely unknown. In our previous study, miR-302a was found to be decreased in cetuximab-resistant cell lines, which promoted the sensitivity of cells to cetuximab, and its expression may be regulated by GATA6. The transcription factor NFIB may be its direct target. In the present study, we intend to: 1. Further investigate the expression of miR-302a in CRC and its function to regulate the sensitivity of cetuximab; 2. To elucidate that GATA6 transcriptionally regulates miR-302a expression and mediates cetuximab sensitivity; 3. To study the downstream molecular regulatory network of miR-302a to inhibit the sensitivity of cetuximab by inhibiting the target molecule NFIB; 4. To utilize PDX mice model, organoid culture and clinically specimens to validate GATA6/miR-302a/NFIB expression patterns and potential therapeutic values. This study is expected to provide a new epigenetic mechanism for understanding cetuximab resistance, providing new targets and therapeutic strategies for reversing cetuximab resistance.