The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death.

Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/-independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.

Kawauchi D ，Takahashi M ，Satomi K ，Yamamuro S ，Kobayashi T ，Uchida E ，Honda-Kitahara M ，Narita Y ，Iwadate Y ，Ichimura K ，Tomiyama A ... -  《-》

ALTA-2: Phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed on alectinib or ceritinib.

Kim ES ，Barlesi F ，Mok T ，Ahn MJ ，Shen J ，Zhang P ，Ou SI ... -  《-》

Efficacy of Ceritinib After Alectinib for ALK-positive Non-small Cell Lung Cancer.

Alectinib is a new standard treatment for treatment-naïve anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC); however, resistance ultimately develops in almost all patients, and data regarding the efficiency of ceritinib for such patients are insufficient. Patients with ALK-positive NSCLC treated at the Kyoto University Hospital from January 2012 to March 2017 were reviewed. Patients who were treated with ceritinib after alectinib were identified, and the efficacy of ceritinib after alectinib was retrospectively evaluated. There were 35 patients with ALK-positive NSCLC, nine of whom received ceritinib after alectinib. The overall response rate to ceritinib was 44%. It was 16% in patients who received ceritinib immediately after alectinib, and 100% in patients who received chemotherapy before ceritinib. The median progression-free survival for patients treated with ceritinib was 4.4 months (95% confidence interval(CI)=1.1-6.5 months). Ceritinib demonstrated a modest clinical benefit after failure of alectinib. Ceritinib may be a reasonable treatment option in this setting.

Yoshida H ，Kim YH ，Ozasa H ，Sakamori Y ，Tsuji T ，Nomizo T ，Yasuda Y ，Yamamoto T ，Ajimizu H ，Hirai T ... -  《-》

A patient with ALK-positive lung adenocarcinoma who survived alectinib-refractory postoperative recurrence for 4 years by switching to ceritinib.

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.

Matsumura Y ，Inomata S ，Yamaguchi H ，Mine H ，Takagi H ，Watanabe M ，Ozaki Y ，Yamaura T ，Fukuhara M ，Muto S ，Okabe N ，Hasegawa T ，Shio Y ，Suzuki H ... -  《-》

Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC.

Dong X ，Fernandez-Salas E ，Li E ，Wang S ... -  《-》