JUN/Cyclin D1通路在胃肠间质瘤对伊马替尼耐药的作用及机制研究

胃肠间质瘤（GIST）是一种罕见的消化系统肿瘤。KIT缺失表达（KIT-）是伊马替尼耐药中除KIT/PDGFRA突变之外一种新的“非经典型耐药”模式，其耐药机制仍不明确。本课题组前期研究发现Cyclin D1在KIT- GIST细胞系与临床标本中均特异性高表达。最近我们通过转录组测序，发现JUN在KIT- GISTs中过表达，与Cyclin D1的过表达明显相关。由此推测JUN可能通过介导Cyclin D1过表达导致KIT- GISTs对伊马替尼耐药。本课题将在前期研究基础上，明确Cyclin D1与KIT- GISTs的临床相关性；进一步探讨JUN通过直接转录机制调控Cyclin D1的过表达导致伊马替尼耐药的机制；最后观察联合伊马替尼与JUN/Cyclin D1抑制剂在逆转伊马替尼耐药中的作用。本研究将为克服KIT缺失表达导致的伊马替尼“非经典型耐药”提供可能的靶点及治疗方式。

Gastrointestinal stromal Tumors (GISTs) are rare tumors of digestive tract. Apart from the mutation of KIT/PDGFRA, loss of KIT expression is another new type of “non-classic resistance patterns”, but its resistance mechanism remains unclear. Our preliminary study showed that specific overexpression of Cyclin D1 existed in both the KIT-independent GIST cell lines and clinical specimen. Moreover, we recently found that JUN expressed strongly in the KIT-independent GISTs which had a significant correlation with the overexpression of Cyclin D1. Thus, we speculate that JUN probably induces overexpression of the Cyclin D1, resulting in imatinib-resistance of KIT-independent GISTs. Based on the abovementioned investigation, our research will: (1) confirm the clinical relevance between Cyclin D1 overexpression and KIT-independent GISTs; (2) explore furtherly overexpression of Cyclin D1, which is regulated by JUN through the direct transcriptional mechanism, results in the imatinib-resistance; (3) reveal the effect of combination of imatinib and JUN/Cyclin D1 inhibitors in the reversal of imatinib-resistance. This study will provide possible therapeutic targets and novel treatment to overcome the “non-classic resistance patterns” due to the loss of KIT expression in the future.