Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.

There have been few advances in the treatment of small-cell lung cancer (SCLC) because of the lack of targets. MCL1, a member of the anti-apoptotic BCL-2 family, may be a treatment target in several cancers, including SCLC. However, whether the expression profile of the anti-apoptotic BCL-2 family affects MCL1 inhibition strategy is unknown. A tissue microarray (TMA) was created from consecutive patients who were diagnosed with SCLC and had previously undergone surgery at Kyoto University Hospital (Kyoto, Japan) between 2001 and 2017. We used S63845, a MCL1 inhibitor, to assess the cytotoxic capacity in SCLC cell lines including a patient-derived cell line in vitro and in vivo. The combination of S63845 with navitoclax, a double BCL-X L /BCL-2 inhibitor, was also employed to examine the comprehensive inhibition of the anti-apoptotic BCL-2 family. Immunohistochemistry of a TMA from patients with surgically resected SCLC demonstrated high MCL1 expression with low BCL-X L and BCL-2 to be the most common expression profile. S63845 was effective in high MCL1-and low BCL-X L -expressing SCLC cell lines. S63845 induced BAKdependent apoptosis in vitro, and the anti-tumor efficacy was confirmed in an in vivo model. Although knockdown of BCL-X L and BCL-2 improved the cytotoxic activity of S63845 and its combination with navitoclax increased the antitumor cytotoxicity, the therapeutic range of S63845 with navitoclax was narrow in in vivo studies. Our study suggests MCL1 inhibition therapy be applied for high MCL1-and low BCL-X L -expressing SCLC patients.

IntroductionIn 2016, an international working group proposed a revised definition and new diagnostic criteria for the acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Based on these criteria, AE-IPF was diagnosed regardless of the presence or absence of a known trigger and categorised as triggered (T-AE) or idiopathic (I-AE) AE-IPF. However, the clinical characteristics of the newly defined AE-IPF and clinical differences between T-AE and I-AE are unresolved.MethodsWe retrospectively analysed 64 patients with AE-IPF (I-AE (42), T-AE (22)) admitted to our hospital over a 10- year period.ResultsI-AE and T-AE cases did not show differences in in-hospital and long-term outcomes (in-hospital mortality: I-AE 52.4%, T-AE 59.1%, p=0.61; long-term mortality: p=0.68). In the I-AE group, significantly more patients received corticosteroid therapy before an AE (I-AE 35.7%, T-AE 4.5%; p=0.01). Significantly more patients in the T-AE group had lung cancer (I-AE 7.1%, T-AE 59.1%, p<0.001). I-AE occurred more frequently in winter while T-AE did not show seasonality. The white blood cell (WBC) count and haemoglobin (Hb) level were independent predictors of in-hospital deaths in I-AE (WBC: OR 1.87; 95% CI 1.09 to 4.95, p=0.01; Hb: OR 0.26, 95%  CI 0.04 to 0.78, p=0.01) but not T-AE.DiscussionWith the introduction of new criteria for AE-IPF, a retrospective study over a 10-year period showed a lack of prognostic difference between I-AE and T-AE. The WBC count and Hb level predicted in-hospital outcome in I-AE cases.

Chronic obstructive pulmonary disease (COPD) may coexist with lung cancer, but the impact on prognosis is uncertain. Moreover, it is unclear whether pharmacological treatment for COPD improves the patient’s prognosis. We retrospectively investigated patients with advanced non-small-cell lung cancer (NSCLC) who had received chemotherapy at Kyoto University Hospital. Coexisting COPD was diagnosed by spirometry, and the association between pharmacological treatment for COPD and overall survival (OS) was assessed. Of the 550 patients who underwent chemotherapy for advanced NSCLC between 2007 and 2014, 347 patients who underwent spirometry were analyzed. Coexisting COPD was revealed in 103 patients (COPD group). The median OS was shorter in the COPD group than the non-COPD group (10.6 vs. 16.8 months). Thirty-seven patients had received COPD treatment, and they had a significantly longer median OS than those without treatment (16.7 vs. 8.2 months). Multivariate Cox regression analysis confirmed the positive prognostic impact of COPD treatment. Additional validation analysis revealed similar results in patients treated with immune checkpoint inhibitors (ICIs). Coexisting COPD had a significant association with poor prognosis in advanced NSCLC patients if they did not have pharmacological treatment for COPD. Treatment for coexisting COPD has the potential to salvage the prognosis.

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