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.

The mechanisms responsible for the development of resistance to alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, are still unclear, and few cell lines are currently available for investigating ALK-rearranged lung cancer. To identify the mechanisms underlying acquired resistance to alectinib, two patient-derived cell lines were established from an alectinib-naïve ALK-rearranged lung cancer and then after development of alectinib resistance. The properties acquired during treatments were detected by comparisons of the two cell lines, and then functional analyses were performed. Coactivation of c-Src and MET was identified after the development of alectinib resistance. Combinatorial therapy against Src and MET significantly restored alectinib sensitivity (17.2-fold). Increased apoptosis, reduction of tumor volume, and inhibition of MAPK and PI3K/AKT signaling molecules for proliferation and survival were observed when the three kinases (Src, MET, and ALK) were inhibited. A patient-derived xenograft from the alectinib-resistant cells indicated that combination therapy with a saracatinib and crizotinib significantly decreased tumor size To confirm the generality, a conventional alectinib-resistant cell line model (H2228-AR1S) was established from NCI-H2228 cells (EML4-ALK variant 3a/b). In H2228-AR1S, combination inhibition of Src and MET also restored alectinib sensitivity. These data reveal that dual salvage signaling from MET and Src is a potential therapeutic target in alectinib-resistant patients. This study demonstrates the feasibility to elucidate personalized drug-resistance mechanisms from individual patient samples.

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.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a high-mortality disease that is difficult to diagnose clinically. Our patient was an 80-year-old woman who came to us due to symptoms of increasing dyspnea. A clinical evaluation showed that she had hypoxemia and pulmonary arterial hypertension without any abnormalities in the major pulmonary arteries, bronchi, or alveoli. A lung perfusion scan showed multiple wedge-shaped perfusion defects. Further examination revealed adenocarcinoma in her right parotid gland with metastasis to the submandibular lymph nodes. We diagnosed her to have PTTM caused by a parotid tumor. The patient survived for 11 months with chemotherapy. An early antemortem diagnosis by minimally invasive examinations will help PTTM patients to survive longer.

Thymic carcinoma is a rare neoplasm with a poor outcome due to its aggressive characteristics. For patients who are not operable, radiation therapy and/or palliative chemotherapy are indicated. However, no optimal chemotherapy regimen has been established. The present study reports the case of a 22-year-old man with advanced lymphoepithelioma-like thymic carcinoma refractory to conventional chemotherapy with carboplatin plus solvent-based paclitaxel (sb-PAC) treatment. The patient was subsequently treated with carboplatin plus nanoparticle albumin-bound paclitaxel (nab-PAC). The treatment resulted in a partial response following three cycles of chemotherapy. Since only grade 3 neutropenia, but no other severe adverse effects, was observed, no dose reduction was required. To the best of our knowledge, the current study is the first to present the response to chemotherapy with carboplatin plus nab-PAC in a patient with lymphoepithelioma-like thymic carcinoma. Considering that no standard treatment has been established in thymic carcinoma, nab-PAC may merit further investigation in this rare, but aggressive disease.