Metastatic Non-Myofibroblastic Sarcoma Harbouring EML4-ALK Fusion—Dramatic Response to ALK Tyrosine Kinase Inhibitors and Development of Resistance Mutations

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Accounts of Chemical Research Pub Date : 2024-08-26 DOI:10.1002/cnr2.2164
Isabella Wilson, Min Qiu, Malinda Itchins, Bin Wang, Min Li Huang, Peter Grimison
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Abstract

Background

Anaplastic lymphoma kinase (ALK) rearrangements are rare in non-myofibroblastic sarcoma and there is limited data on the efficacy of ALK tyrosine kinase inhibitors (TKIs) and mechanisms of resistance in these patients.

Case

A 58 year-old man with metastatic non-myofibroblastic sarcoma was found to have an EML4-ALK fusion on molecular sequencing. After progression on first line systemic therapy with doxorubicin, the patient received alectinib, a second generation ALK inhibitor, and had a marked clinical and radiological response. He progressed after 5 months of treatment. Repeat lung biopsy identified the emergence of an ALK I1171N resistance mutation. He was then treated with lorlatinib, again with rapid clinical improvement and significant partial radiological response. He progressed after 4 months, at which time a repeat lung biopsy identified a new ALK kinase domain mutation G1202R. The patient was subsequently treated with chemotherapy, though unfortunately died shortly after due to rapidly progressive disease.

Conclusion

This case report adds to a body of evidence demonstrating the potential transformative response to targeted therapy in non-lung solid organ tumours harbouring ALK fusions. This is the first description tracking the development of resistance mutations in a patient with non-myofibroblastic sarcoma and questions the utility of the presence of G1202R mutation as a marker of lorlatinib sensitivity in non-lung ALK rearranged tumours, contrary to experience in lung cancer.

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携带 EML4-ALK 融合基因的转移性非肌成纤维肉瘤--对 ALK 酪氨酸激酶抑制剂的剧烈反应和抗性突变的发展。
背景:无性淋巴瘤激酶(ALK)重排在非肌纤维母细胞肉瘤中非常罕见,有关ALK酪氨酸激酶抑制剂(TKIs)的疗效和这些患者的耐药机制的数据非常有限:病例:一名患有转移性非纤维母细胞肉瘤的58岁男子在分子测序中发现EML4-ALK融合。在接受多柔比星一线系统治疗出现进展后,患者接受了第二代 ALK 抑制剂阿来替尼,并出现了明显的临床和放射学反应。治疗5个月后,他的病情有所进展。重复肺活检发现出现了 ALK I1171N 耐药突变。随后,他接受了洛拉替尼(lorlatinib)治疗,再次获得快速临床改善和显著的部分放射学反应。4 个月后他的病情有所进展,此时再次进行肺活检发现了新的 ALK 激酶域突变 G1202R。患者随后接受了化疗,但不幸的是,由于病情进展迅速,他不久后就去世了:本病例报告补充了大量证据,证明靶向治疗对携带 ALK 融合的非肺实体器官肿瘤具有潜在的转化性反应。这是对非肌纤维肉瘤患者耐药性突变发展的首次追踪描述,并质疑了将G1202R突变作为非肺部ALK重排肿瘤中洛拉尼敏感性标志物的实用性,这与肺癌的经验正好相反。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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