Non-small cell lung cancer patient with a rare UGP2-ALK fusion protein responded well to alectinib: a case report

Abstract

Several rare anaplastic lymphoma kinase (ALK) fusions have been identified in patients with non-small cell lung cancer (NSCLC); however, their treatment is not currently uniform. alectinib has been commonly used to treat rare ALK fusions in patients with NSCLC. This is the first study to report the occurrence of a uridine diphosphate-glucose pyrophosphorylase 2 (UGP2)-ALK fusion in a patient with NSCLC. The patient, who was hospitalized because of shortness of breath lasting 20 days, showed hydrothorax of the left lung under a computerized tomography chest scan. Pathological histology revealed lung adenocarcinoma in the patient. The UGP2-ALK mutation was found by next-generation sequencing. Subsequently, the patient was administered alectinib, and thereafter, the tumor lesion was observed to gradually shrink over the follow-up period. Progression-free survival reached 10 months as of the follow-up date, with no adverse events detected. This case report provides valuable insights into the clinical management of NSCLC patients with UGP2-ALK fusions. Moreover, alectinib is confirmed to be an appropriate therapeutic agent for such patients.

Introduction

Although not as common as epidermal growth factor receptor mutations, mutations in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung cancer (NSCLC) cases [1]. Various ALK fusions have been identified, including fusions with EML4, KIF5B, KLC1, and TPR; however, EML4-ALK is the most common mutation type among ALK fusions [2,3]. International guidelines recommend first-line targeted therapy for patients with NSCLC with ALK rearrangements [4]. Alectinib is typically used as a first-line therapeutic agent, as it has better progression-free survival (PFS) and fewer adverse reactions than other ALK-tyrosine kinase inhibitors (ALK-TKIs), although lorlatinib may have more favorable PFS as a second ALK-TKI [5].

However, with limited clinical samples and data for rare ALK mutations in NSCLC, it is difficult to choose whether to use chemotherapy or ALK-TKIs as a treatment, although many reports have indicated that alectinib is a selectable treatment for rare ALK mutations in NSCLC.

This study is the first report on a patient with NSCLC arising from a uridine diphosphate-glucose pyrophosphorylase 2 (UGP2)-ALK fusion mutation, a rare ALK fusion. UGP2 is a key enzyme that regulates glycogen biosynthesis. The mutation was confirmed using targeted next-generation sequencing (NGS), and the patient showed a positive response to treatment with alectinib.

Case description

A Chinese woman with a persistent cough for over 3 years was hospitalized in March 2022 because of shortness of breath lasting 20 days. A computerized tomography (CT) chest scan on 7 March 2022, revealed hydrothorax of the left lung, left lung atelectasis, and enlarged mediastinal lymph nodes. Laboratory findings showed that the levels of carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), and cancer antigen 125 (CA125) in the patient were 7.60 ng/ml, 4.83 ng/mL, and 52.00 U/mL, respectively. Closed drainage of the left thoracic cavity was performed. Values for CEA, CYFRA, and CA125 in the patient’s pleural fluid were 29.20 ng/ml, 428.00 ng/ml, and 1687.00 U/ml, respectively. The electrocardiogram indicated that the patient had paroxysmal atrial flutter. We performed an ultrasound-guided lesion puncture biopsy of the left lung, and the patient was diagnosed with lung adenocarcinoma by pathological histology. Immunohistochemistry was performed for TTF-1 (+), vimentin (+), Ki-67 (20%), CK (+), P40 (–), CK5/6 (–), Syn (–), EMA (–), Pax-8 (–), and ALK (D5F3 Ventana IHC) (+) (Fig. 1). Tumor cells were found in the pleural fluid by pathological cytology, indicating pleural metastasis (Fig. 1). After full drainage of the pleural fluid, the left pleural cavity of the patient was injected with streptococcal A 5 KE, bupivacaine 5 mL, and cis-platinum 10 mg, achieving cavity-sealing therapy (a treatment inhibiting malignant pleural effusion by making the pleura adhesion) followed by removal of the thoracic drainage tube. A subsequent CT scan showed a large lesion (6.2 × 4.1 cm) in the left upper lobe on 17 March 2022. However, drainage of pleural fluid did not cause anesis atrial flutter even if β-blocker was also used.

Fig. 1.

Histopathology of the patient’s lung tissue. (a) Histopathology of the lung adenocarcinoma (200× magnification). (b) Histopathology of the lung adenocarcinoma (100× magnification). (c) Tumor cells found in the pleural fluid of the left lung. (d) Nuclear image and DNA index of the pleural hydrocyte.

NGS was performed on the pulmonary tissue, confirming the presence of a rare, novel ALK fusion (UGP2-ALK) mutation that has not been previously reported (Fig. 2). After a thorough and detailed comprehensive group discussion of economy, safety, and effectiveness, the patient was informed that UGP2-ALK is a rare ALK fusion for which there are available treatments and was administered alectinib 600 mg twice daily from 21 March 2022. After 4 weeks, CT scans showed that the left lung lesion was significantly reduced in size (2.4 × 3.2 cm) and the hydrothorax decreased, which represented a partial response (PR) according to RECIST 1.1 criteria. Continued shrinkage of the tumor lesion was observed on CT examination after 2, 6, 9, and 10 months at subsequent follow-ups (Fig. 3). Meanwhile, the pleural fluid continued to decrease and was almost completely absorbed by 28 September 2022. By the last follow-up visit date, the patient had achieved 10-month PFS, and no Grade 3 adverse events were detected (the patient had reached 13 months of PFS at the time of writing this manuscript). In addition, no arrhythmia events occurred.

Fig. 2.

Integrative genomics viewer snapshot of the fusion between UGP2 and ALK as revealed by next-generation sequencing (NGS).

Fig. 3.

Chest CT showing the changes in the patient’s lung adenocarcinoma. The tumor in the left lung reduced in size at each follow-up. Pleural fluid in the left lung continued to decrease until it was almost completely absorbed.

Discussion

The ALK gene belongs to the insulin receptor superfamily and encodes the ALK protein. ALK fusions contain exons 20–29 of ALK, which encode the entire C-terminal kinase domain, and the N-terminal portions of ALK fusions in NSCLC include numerous fusion partners. To date, over 90 ALK fusion partners have been described [6]. Functional domains within the fusion partner or oligomerization at subcellular locations mediate the dimerization of ALK. ALK kinase domains are activated through phosphorylation in a ligand-independent fashion [7]. Finally, ALK activates multiple signaling pathways. Different ALK fusion partners confer differential oncogenic properties.

We found that UGP2 and ALK fused to form a new fusion protein, UGP2-ALK, which is a rare ALK fusion not previously reported. Mutations in UGP2 have been reported in cancer-associated diseases but not in NSCLC. The activation of uridine diphosphate (UDP)-glucose in many anabolic pathways is catalyzed by UGP2, which is the only enzyme capable of converting glucose 1-phosphate to UDP-glucose in mammalian cells [8]. UGP2 is also reported to promote cell migration and invasion by increasing glycogen production. There may be potential mechanisms underlying the involvement of UGP2 in the migration, invasion, growth, and occurrence of cancer cells [9].

We speculate that UGP2-ALK fusion may form a dimer of ALK fusion proteins and activate the ALK kinase domain through phosphorylation, which activates multiple signaling pathways regulating the growth and proliferation of cells, which in turn can affect cellular phenotypes and responses to targeted therapies [10]. Patients with type 2 diabetes have an increased risk of cancer, but the specific mechanism behind this risk remains unclear [11]. The patient in our study had type 2 diabetes and a UGP2-ALK fusion, which may be related to glycogen biosynthesis. However, whether UGP2 is involved in the development of type 2 diabetes remains to be confirmed.

Because of the lack of large sample data, the treatment of rare ALK mutations in NSCLC deserves more attention and discussion. It is unclear how ALK-TKIs influence NSCLC patients with rare ALK fusions, with some of these patients showing significant effects after treatment with ALK-TKIs (including alectinib) [12,13]. Next-generation ALK-TKIs may increase overall survival (OS) compared with current ALK-TKIs that can be used as the first choice in patients with advanced ALK-rearranged NSCLC [14].

Alectinib, a second-generation ALK-TKI, is used as a first-line therapy in patients with ALK rearrangement, providing longer PFS and better safety than crizotinib [15]. In the present case, sustained PR was observed in the patient with NSCLC and UGP2-ALK fusion after treatment with alectinib, with PFS reaching 10 months by the latest follow-up date. Other cases of rare ALK fusions that have also been treated with alectinib have shown positive outcomes [12,16].

In an analysis comparing ALK-TKIs and platinum-based chemotherapy in patients with advanced NSCLC with ALK mutations, alectinib showed the highest OS and lowest incidence of Grade 3 adverse safety events [17]. In the present case study, PFS reached 10 months, and no Grade 3 adverse events were observed during follow-up. However, there have been reports of hemolytic anemia induced by first-line alectinib treatment in patients with ALK-positive NSCLC, with hemoglobin returning to normal levels after gradual discontinuation [18].

Conclusion

This is the first report of a UGP2-ALK fusion in a patient with NSCLC who received alectinib treatment. Sustained PR was observed, and PFS of the patient reached 10 months. However, the relationship between UGP2, type 2 diabetes, and cancer remains unknown and requires further research. In addition, alectinib may be a preferred choice for rare ALK fusions in NSCLC patients, and further research and efforts are needed to determine other rare ALK fusions and their appropriate treatment. We will continue to follow up with the patient to monitor her condition.

Acknowledgements

We would like to thank the patient and her family for agreeing to publish this case study.

This study was supported by the National Natural Science Foundation of China (No. 82103537).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Conflicts of interest

There are no conflicts of interest.