A novel HIP1-ALK fusion variant in lung adenocarcinoma showing resistance to Crizotinib

Anaplastic lymphoma kinase (ALK) rearrangements have been identified in 3–5 % non-small cell lung cancer (NSCLC) patients, with echinoderm microtubule associated protein like 4 gene (EML4) being the most common fusion partner. Huntingtin-interacting 1 (HIP1) has recently as a novel partner fused to ALK NSCLC three different HIP1-ALK variants reported (H28:A20), (H21:A20) and (H30:A20) date [1Fang D.D. Zhang B. Gu Q. Lira M. Xu Sun H. Qian Sheng W. Ozeck Wang Z. C. Chen X. K.X. Li J. S.H. Christensen Mao Chan C.C. HIP1-ALK, variant that responds crizotinib.J. Thorac. Oncol. 2014; 9: 285-294Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 2Hong Kim R.N. Song J.Y. Choi S.J. Oh E. M.E. Takeuchi K. Han Y.L. adenocarcinoma.J. 419-422Abstract (49) 3Ou Klempner Greenbowe J.R. Azada Schrock A.B. Ali S.M. Ross J.S. Stephens P.J. Miller V.A. Identification of Non-Small-Cell Lung Cancer discovery I1171 (I1171N/S) mutations two ALK-rearranged patients resistance Alectinib.J. 1821-1825Abstract (75) Scholar]. Analogous well-known multiple EML4-ALK, it is likely other also exist [[3]Ou Herein, we report (H19:A20) patient adenocarcinoma. Contrary previous reports harboring responded well Crizotinib, present case displayed primary clinical Crizotinib. A 56-year-old Chinese women without smoking history was referred our hospital for waist pain November 2019. Computed tomography (CT) showed bone destruction soft tissue mass close left pedicle fourth lumbar vertebra. Further positron emission tomography–computed (PET-CT) revealed (right 6th anterior rib, 7th cervical vertebra, st/4th vertebra), lymph node enlargement (including right hilum, mediastinal trachea, upper mediastinum, clavicle area, internal mammary artery, axillary) nodules lower lobe both lungs (Fig. 1A). No brain metastasis detected. Palliative metastasectomy spine performed on 19, 2019 postoperative pathological examination atypia cells fibrocartilage tissue. Immunohistochemistry (IHC) analysis indicated positive expression Napsin A, TTF-1, CK7 ALK, suggesting adenocarcinoma 1B). Subsequently, next-generation sequencing (NGS) based 168-gene panel (Burning Rock Biotech, Guangzhou, China) specimens, which (H19:A20, an abundance 1.67 %). The retained entire tyrosine domain 2) co-mutation not administered Crizotinib (250 mg, twice day) first-line therapy since She complained progressive dyspnea unbearable 2 months later. subsequent chest CT scan massive pleural effusion lung, indicating disease progression during treatment. Pleural drained second NGS 520-gene aiming explore mechanism. Again, 6.23 %) detected, yet neither point-mutation nor alternative pathway activation revealed. then Alectinib (600 January 2020. Follow-up scans continuously decreased reduced target lungs. progression-free survival (PFS) exceeded 9 till now 1C).Fig. 2Identification patient. (A) Sequencing reads HIP1 were visualized by Integrative Genomics Viewer (IGV). (B) schematic map showing structure HIP1- locus. Exons 1–19 (blue) exons 20–29 (yellow) through intron19 ALK.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Fang et al. [[1]Fang Scholar] demonstrated (H28; A20) sensitive treatment vitro, Hong [[2]Hong (H21; no recurrence or 15 follow-up, Ou described response inhibitors including We another breakpoint whose previously identified. In this case, aggravation symptoms, heterogeneous molecular group HIP1–ALK may lead responses Heterogeneity only partners but variants. Typically, efficacy ALK-EML4 differed, according types Yoshida had significantly longer PFS than non–variant [[4]Yoshida T. Oya Y. Tanaka Shimizu Horio Kuroda Sakao Hida Yatabe Differential crizotinib duration among ALK-Positive non-small-cell cancer.J. Clin. 2016; 34: 3383-3389Crossref (189) proposed explanation Heuckmann various parts EML4 affected stability, inhibitor-induced degradation, drug sensitivity [[5]Heuckmann J.M. Balke-Want Malchers F. Peifer Sos M.L. Koker Meder L. Lovly C.M. Heukamp L.C. Pao Kuppers R. Thomas R.K. stability inhibitor EML4-ALK variants.Clin. Res. 2012; 18: 4682-4690Crossref (205) specific mechanism still needs further investigation, remains be explored. displays significant capability detect fluorescence situ hybridisation (FISH)-negative, FISH-unusual type NSCLC. Currently, more 90 discovered. Large-scale data relevant ALK-TKIs these rare fusions are fully available. Clinicians around world encouraged information breakpoints, (TKIs) used routine method. Reports such incidents will provide better understanding applications reference future authors grateful financial grants from Zhejiang Provincial natural Science Foundation China ( LY16H160006 ) Hangzhou Technology Bureau 20160533 B72 ).