Targeting EML4-ALK gene fusion variant 3 in thyroid cancer

Abstract

Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a six-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks’ use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

“…With lorlatinib, the patient achieved ongoing PR after seven months of therapy. The study showed that lorlatinib was more efficient than the already administered crizotinib in vivo and in vitro [ 155 ].…”

Remarkable response to alectinib for metastatic papillary thyroid cancer with STRN-ALK fusion: A case report

“…Aydemirli et al. reported a partial response in an EML-ALK fusion patient treated with lorlatinib after resistance to crizotinib ( 7 ). de Salins et al.…”

EML4‑ALK fusion gene in non‑small cell lung cancer (Review)

“…Lung cancer is classified into two histological groups: SCLC (~17.3%) and NSCLC (~82.7%) (46)(47)(48), of which lung adenocarcinoma and lung squamous cell carcinoma are the major subgroups (48). Since the EML4-ALK fusion gene was discovered in lung adenocarcinoma in 2007, it has been considered to be a characteristic gene of lung cancer; however, in recent years, it has gradually been detected in other types of cancer, such as thyroid cancer, gastric stromal tumors and leiomyoma (11,(49)(50)(51). According to a previous study, the oncogenic fusion of EML4-ALK is present in 3-5% of NSCLC (27).…”