Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing

• Main Authors: Zhang C, Wang Z, Zhuang R, Guo X, Feng Y, Shen F, Liu W, Zhang Y, Tong H, Sun W, Liu J, Wang G, Dai C, Lu W, Zhou Y
• Format: Article
• Language: English
• Published: Dove Medical Press 2020-10-01
• Series: OncoTargets and Therapy
• Subjects: inflammatory myofibroblastic tumor; crizotinib resistance; alectinib resistance; alk l1196q; sonic hedgehog pathway
• Online Access: https://www.dovepress.com/efficacy-and-resistance-of-alk-inhibitors-in-two-inflammatory-myofibro-peer-reviewed-article-OTT
• ISSN: 1178-6930

Chenlu Zhang,1 Zhiming Wang,1 Rongyuan Zhuang,1 Xi Guo,1 Yi Feng,1 Feng Shen,1 Wenshuai Liu,2 Yong Zhang,3 Hanxing Tong,3 Wending Sun,4 Jun Liu,4 Guan Wang,4 Chun Dai,4 Weiqi Lu,3 Yuhong Zhou1 1Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of General Surgery, Shanghai Public Health Clinical Center, Shanghai, People’s Republic of China; 3Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 4GenomiCare Biotechnology Co. Ltd, Shanghai, People’s Republic of ChinaCorrespondence: Weiqi LuDepartment of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, People’s Republic of ChinaEmail [e-mail] ZhouDepartment of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, People’s Republic of ChinaEmail [e-mail]: We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then experienced recurrence or progression of the disease. During the treatment, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were applied to monitor potential drug-induced gene mutation and expression changes. A novel, secondary mutation in ALK exon 23 (L1196Q) was identified in patient 1 after alectinib resistance developed. Guided by this result, a newer ALK inhibitor, ceritinib was prescribed. The patient was able to achieve a partial response (PR) and is in good condition as of the manuscript date. On the contrary, there was no secondary mutation identified in ALK in patient 2 after drug resistance. While the expression of PTCH1, a negative regulator of the sonic hedgehog (SHH) signaling pathway, was significantly reduced at the time after the treatment with crizotinib before that of alectinib. The expression of PTCH1 was also reduced after the treatment with alectinib. It was reported that ALK can exert its biological functions partially by activating SHH signaling pathway. The down-regulation of PTCH1 suggests the compensatory activation of SHH pathway may cause resistance to ALK inhibitors in IMT. Going forward, monitoring gene mutation and expression changes through DNA and RNA sequencing will be able to offer opportunities to investigate potential mechanisms of drug resistance and will help to achieve precise prescription for better treatment outcomes.Keywords: inflammatory myofibroblastic tumor, crizotinib resistance, alectinib resistance, ALK L1196Q, sonic hedgehog pathway