Introduction: Although the efficacy of molecular targeted therapies varies across actionable genomic alterations in NSCLC, comparisons within a single real-world cohort remain limited. Methods: We conducted a retrospective multi-institutional study of 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy from 2017 to 2023. Patients were classified into the following three genomic groups: EGFR mutations (group A), ALK/ROS1/RET fusion oncogenes (group B), and others, including MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations (group C). Treatment efficacy and safety were compared across the groups. Results: Treatment outcomes differed between the subgroups. Group B demonstrated the highest objective response rate (85.8%) and the longest median real-world progression-free survival (rwPFS; 42.5 mo); median overall survival (OS) was not reached. Group A had intermediate outcomes. Group C exhibited the shortest rwPFS (9.2 mo), poorer OS, and higher rates of treatment discontinuation due to adverse events. Such hierarchical differences were observed in patients with baseline central nervous system metastases and in those receiving first-line treatment. In multivariate analysis, genomic subgroup remained associated with rwPFS and OS, with fusion-driven tumors maintaining superior outcomes irrespective of other factors. Conclusions: This large real-world analysis yielded a hierarchy of therapeutic benefits across actionable genomic alterations in NSCLC. Patients with fusion-driven tumors benefited from targeted therapy, whereas those with EGFR-mutated tumors had intermediate outcomes. Treatment of patients with MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations had limited efficacy and higher toxicity, underscoring the need for improved therapeutic strategies.

e20712 Background: Molecular targeted therapies have transformed the management of non–small cell lung cancer (NSCLC) with actionable genomic alterations. However, direct comparisons of treatment outcomes across different genomic subtypes within a single real-world cohort remain limited. We evaluated the relative efficacy and safety of targeted therapies across major actionable genomic alterations in a large Japanese real-world population. Methods: This multicenter retrospective study included 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy between 2017 and 2023. Patients were classified into three genomic groups: EGFR mutations (Group A, n = 659), fusion oncogenes involving ALK/ROS1/RET (Group B, n = 106), and other actionable alterations including MET exon 14 skipping, BRAF V600E, and KRAS G12C (Group C, n = 45). Treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety, were analyzed using Kaplan–Meier methods and multivariable Cox regression. Results: The median follow-up was 24.9 months overall (Group A 25.6, Group B 27.3, Group C 16.1). A total of 580 progression events and 398 deaths were observed. ORR differed significantly among groups (74.1% in Group A, 85.8% in Group B, and 68.9% in Group C; P = 0.014). Median PFS was 17.5 months in Group A, 42.5 months in Group B, and 9.2 months in Group C (P < 0.001). Median OS was not reached in Group B, compared with 39.3 months in Group A and 22.7 months in Group C (P < 0.001). In multivariable analyses adjusting for clinical covariates, genomic subgroup remained independently associated with both PFS and OS, with fusion-driven tumors demonstrating consistently superior outcomes. EGFR-mutated tumors showed intermediate outcomes, whereas Group C exhibited limited efficacy and higher treatment discontinuation due to adverse events. Conclusions: In this large Japanese real-world cohort, a clear hierarchy of therapeutic benefit across actionable genomic alterations was observed. Fusion oncogene–driven NSCLC derived exceptional and durable benefit from targeted therapy, EGFR-mutated tumors demonstrated intermediate outcomes, and MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations remained associated with limited efficacy and higher toxicity. These findings underscore the clinical importance of genomic subtype–based treatment strategies and highlight unmet needs in selected molecular subsets.

Background/Aim: Chemoresistance to paclitaxel (PTX) significantly ameliorates therapeutic efficacy in patients with non-small cell lung cancer (NSCLC), especially in advanced stages, deteriorating the progression free and overall survival rates. One of the critical mechanisms contributing to drug resistance is the excretion of PTX from target cells via efflux pumps. Ivermectin was developed as a bactericidal agent against parasites; however, it has recently been shown to inhibit the proliferation of human cancer cells. Hence, we aimed to evaluate the therapeutic potential of ivermectin in combination with PTX and investigate the molecular mechanisms by which ivermectin overcomes PTX resistance. Materials and Methods: We assessed the antitumor effects of ivermectin in A549 cells treated with or without PTX. We also established PTX-resistant cells using this cell line and explored the underlying mechanisms. Additionally, we evaluated whether ivermectin attenuates PTX-resistance with the retrieval of drug sensitivity. Results: Combined treatment of A549 cells with PTX and ivermectin inhibited cell growth. These cells acquired chemoresistance upon long-term exposure to gradually increasing PTX concentrations, which was accompanied by ABCB1 mRNA up-regulation, and subsequent overproduction of P-glycoprotein (P-gp). Consistent with this, P-gp overexpression resulted in a PTX-resistant phenotype. Notably, the simultaneous ivermectin treatment during the gradual exposure completely abolished P-gp expression, leading to an increased intracellular PTX concentration and sustained PTX sensitivity. Ivermectin was found to regulate P-gp expression via the EGFR/ERK/Akt/NF-& kgreen;B pathway. Conclusion: Combined highlighting a novel therapeutic avenue for drug repurposing.

Background: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We con-ducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. Methods: Chemotherapy-nai & BULL;ve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle.Results: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively.Conclusion: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. Clinical trial registration number: UMIN000008189.& COPY; 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

IPF is associated with an increased risk of lung cancer, with cumulative incidence rates of 3.3% and 15.4% at 1 and 5 years of follow-up, respectively. The prognosis for lung cancer patients with IPF (IPF-LC) is worse than that for patients with IPF alone, mainly because of the progression of lung cancer and complications following treatment. In addition, promising therapeutic targets for IPF-LC have not been identified. This study investigated the genomic profiles of lung cancer patients with idiopathic pulmonary fibrosis, mechanism of carcinogenesis, and potential therapeutic targets. We analyzed 29 matched, surgically resected, cancerous/non-cancerous lung tissues (19 IPF-LC and 10 non-IPF-LC) by whole exome sequencing and bioinformatics analysis and established a medical-engineering collaboration with the department of engineering. In IPF-LC, cell adhesion molecule 1 (CADM1) and spindle component 25 (SPC25) were mutated at a frequency of 47% (9/19) and 53% (10/19), respectively. Approximately one-third (7/19; 36%) of IPF-LC had both mutations. Pathway analysis revealed that these two genes are involved in transforming growth factor- β1 (TGF- β1) signaling. CADM1 and SPC25 gene mutations decreased the expression of CADM1 and increased that of SPC25 showing TGF- β1-induced epithelial-to-mesenchymal transition and cell proliferation in lung cancer cells. Paclitaxel and DNA methyltransferase 1 (DNMT1) inhibitor suppressed SPC25 expression and SPC25 expression was associated with sensitivity of paclitaxel. Here, we showed that CADM1 and SPC25 gene mutations may be novel diagnostic markers and therapeutic targets for IPF-LC.

Thymic carcinoma is a relatively rare type of malignant tumor. The present retrospective study evaluated the efficacy and safety of carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of advanced thymic carcinoma. The study included data from 12 patients with advanced thymic carcinoma treated in the Nippon Medical School Hospital (Tokyo, Japan). Response to treatment, patient survival and treatment safety were assessed. The objective response rate was 66.7% (8/12 patients). Disease control was achieved in 11 patients (91.7%). At the median follow-up time of 27.6 months (range, 6.2-75.1 months), the median progression-free survival and median first-line overall survival times were 16.7 months [95% confidence interval (CI), 13.2-37.7] and 14.3 months (95% CI, 4.7-54.6), respectively. There was no occurrence of febrile neutropenia or treatment-related death. The results of the present study showed that carboplatin plus nanoparticle albumin-bound paclitaxel was effective and safe. Therefore, it is a promising chemotherapy regimen for the treatment of advanced thymic carcinoma.

Background Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) inhibitors in SCLCs. Methods To identify key factors in the chemoresistance of SCLCs, we established four cell lines resistant to etoposide or an active metabolite of irinotecan, SN-38, from SCLC cell lines and evaluated RNA profiles using parental and newly established cell lines. Results We found that the drug efflux protein, ATP-binding cassette sub-family B member 1 (ABCB1), was associated with resistance to etoposide, and ATP-binding cassette sub-family G member 2 (ABCG2) was associated with resistance to SN-38 by RNA sequencing. The inhibition of ABCB1 or ABCG2 in each resistant cell line induced synergistic apoptotic activity and promoted drug sensitivity in resistant SCLC cells. The ABC transporter inhibitors, elacridar and tariquidar, restored sensitivity to etoposide or SN-38 in in vitro and in vivo studies, and promoted apoptotic activity and G2-M arrest in resistant SCLC cells. Conclusions ABC transporter inhibitors may be a promising therapeutic strategy for the purpose of overcoming resistance to topoisomerase inhibitors in patients with SCLC.

IntroductionTo investigate the genomic profiles of patients with lung cancer with idiopathic pulmonary fibrosis (IPF-LC), mechanism of carcinogenesis, and potential therapeutic targets.MethodsWe analyzed 29 matched, surgically resected, cancerous and noncancerous lung tissues (19 IPF-LC and 10 non–IPF-LC) by whole-exome sequencing and bioinformatics analysis and established a medical-engineering collaboration with the Department of Engineering of the Tokyo University of Science.ResultsIn IPF-LC, CADM1 and SPC25 were mutated at a frequency of 47% (9 of 19) and 53% (10 of 19), respectively. Approximately one-third of the IPF-LC cases (7 of 19; 36%) had both mutations. Pathway analysis revealed that these two genes are involved in transforming growth factor-β1 signaling. CADM1 and SPC25 gene mutations decreased the expression of CADM1 and increased that of SPC25 revealing transforming growth factor-β1–induced epithelial-to-mesenchymal transition and cell proliferation in lung cancer cells. Furthermore, treatment with paclitaxel and DNMT1 inhibitor suppressed SPC25 expression.ConclusionsCADM1 and SPC25 gene mutations may be novel diagnostic markers and therapeutic targets for IPF-LC.

Results: In all, 435 patients were enrolled in this study.The objective response rate and disease control rates were 22.3%, and 54.9%, respectively.Median progression-free survival(PFS) was 3.4months (95%CI: 2.8to 4.2).Overall survival(OS)since ICI therapy was 13 months (95% CI: 10.8 to 15.4).Poor PS(HR: 2.56, 95% CI: 1.93 to 3.40);p <0.01),bone metastasis (HR: 1.42, 95% CI: 1.10 to 1.83; p = 0.007),lung metastasis(HR: 1.28, 95% CI: 1.02 to 1.62; p = 0.032), were correlated with poor OS, and skin toxicity(HR: 0.40, 95% CI: 0.25 to 0.62; p <0.01), were correlated with good OS by multivariate analyses.Patients with irAE (immune-related adverse events) has significantly longer PFS (5.2 and 2.6 months, respectively; p <0.01) and OS (16.3 and 10.8 months, respectively; p <0.01).Good PS and skin toxicity were significantly related to patients with long PFS ( over 2years).Conclusions: The real-world data of ICI monotherapy at any line showed background factors of long-term survival patients treated with ICI monotherapy, such as PS status, bone metastasis, lung metastasis, especially, skin toxicity.

Abstract Small cell lung cancer (SCLC) is a highly aggressive disease with median survival of <2 years. Most patients respond initially to the topoisomerase inhibitors, resistance rapidly emerges. The purpose is overcoming the resistance of the topoisomerase inhibitors in SCLCs. To identify the key factors for the resistance of the topoisomerase I (SN38) or II (VP-16) inhibitors in SCLCs, we analyzed MTS cell proliferation assay. We identified 8 sensitive cell lines and 2 resistant cell lines. We established 4 resistant cell lines by continuous exposure to increasing concentrations of SN-38 or VP-16 stepwise. RNA sequencing was performed using the established cell lines to discover novel therapeutic targets associated with the resistance to topoisomerase inhibitors. We found that whenever the drug efflux protein ATP-binding cassette transporter B1 (ABCB1) was associated the with resistance of VP-16, ATP-binding cassette super-family G member 2 (ABCG2) was associated with the resistance of SN-38. The silencing of ABCG2 or ABCB1 in every resistant cell line, could induce synergistic apoptosis of every cell line. Elacridar and tariquidar which are glycoprotein inhibitors, recovered the sensitivity of SN38 or VP-16 in every resistant line, increased expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and promoted G2/M arrest and apoptosis. Furthermore, we are going to analyze the expressions of ABCG2 and ABCB1 in serum before and after the treatment of VP-16 or CPT-11. These results suggested the glycoprotein inhibitors, which phase I study is ongoing, could be a promising therapeutic strategy for the purpose of preventing the resistance of topoisomerase inhibitors in SCLCs. Citation Format: Rintaro Noro, Miwako Omori, Aya Fukuizumi, kuniko Matsuda, Mariko Hirao, Satoshi Takahashi, Natsuki Takano, Shinji Nakamichi, Teppei Sugano, Akihiko Miyanaga, Yuji Minegishi, Masahiro Seike, Kaoru Kubota, Akihiko Gemma. The glycoprotein inhibitors overcome the resistance of the topoisomerase inhibitors in small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3068.

Idiopathic pulmonary fibrosis (IPF) is reportedly associated with an increased risk of lung cancer. However, optimal diagnosis and treatment for lung cancer associated with IPF remains unclear. In this study, we aimed to clarify the mechanism of carcinogenesis and progression in lung cancer with IPF. We used tumor tissues and adjacent non-tumor lung tissues from 29 lung cancer patients who had undergone complete surgical resection at Nippon Medical School Hospital between 2013 and 2017. Whole-Exon Sequencing was performed on 29 paired samples, consisted of 19 lung cancers with IPF (IPF group) and 10 lung cancers with normal lung (non-IPF group). The candidate gene alterations discriminating between the IPF and non-IPF group, were identified using the random-forest method, RelifF method along with the data from Catalogue Of Somatic Mutations In Cancer (COSMIC). Twenty-five gene alterations were specifically found in IPF tissues and/or tumor tissues with IPF. Whenever 5 of 25 genes including MUC2 and TTF1, were altered in both IPF tissues and tumor tissues, 20 of 25 genes including CADM1, were altered in only tumor tissues. We are undergoing the validation study using other tissues in independent cohorts. Among the candidate genes, Cell adhesion molecule genes (CADM1) gene alterations were frequently found in 15 out of 19 in only tumor tissues with IPF. The CADM1 protein expression was decreased in tumors than in non-tumor fibrotic tissues by western blotting. The CADM1 induced the epithelial-mesenchymal transition (EMT) on the multifunctional cell process involved in the pathogenesis of fibrosis in vitro study. Whenever the down-regulation of CADM1 was frequently detected in various human cancers through its allelic loss as well as hypermethylation within promoter region in addition to inactivate gene mutation, the up-regulation of CADM1 was frequently detected in paired IPF tissues. The CADM1 may be a target candidate in lung cancer associated with IPF.Citation Format: Rintaro Noro, Akihiko Miyanaga, Aya Fukuizumi, Shinobu Kunugi, Teppei Sugano, Miwako Omori, Yuji Minegish, Jitsuo Usuda, Masahiro Seike, Kaoru Kubota, Mamiko Hirao, Kuniko Matsuda, Akihiko Gemma. Genomic profiling of lung cancer associated with idiopathic pulmonary fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1602.

Gut microbiota serves an important role in shaping systemic immune responses. Antibiotics cause changes in the gut microbiota that may influence the efficacy of cancer immunotherapy. In the present study, a retrospective analysis of the data from 90 patients treated with nivolumab for non-small cell lung cancer (NSCLC) was conducted. A total of 13 patients were treated with antibiotics prior to nivolumab therapy. The median progression-free survival time in patients treated with antibiotics was 1.2 months [95% confidence interval (CI), 0.5-5.8], while the time for patients who were not treated with antibiotics was 4.4 months (95% CI, 2.5-7.4). The median overall survival time in patients treated with antibiotics was 8.8 months, while it was not reached in those not treated with antibiotics, respectively. The differences between the survival curves with regard to PFS and OS were statistically significant (P=0.04 and P=0.037, respectively). However, in multivariate analysis, no statistically significant association was indicated between survival and prior antibiotic use, although a certain trend concerning the negative influence of antibiotic use was conveyed.

Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4 weeks. Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1–6). Four patients (12.1%; 95% confidence interval 3.4–28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3 months, 19.8 months, and 55.4%, respectively. The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy.

We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines in a 73-year-old woman who was admitted to our hospital because of dyspnea and an abnormal shadow on a chest radiograph. She had received treatment with numerous drugs, including the herbal medicines Seisin-renshi-in, Chotosan, Rikkunshi-to, and Shakuyakukannzo-to. Chest radiography revealed diffuse ground-glass shadows in both lungs, and bronchoalveolar lavage fluid was progressively hemorrhagic. A culture of the fluid showed no evidence of microorganisms. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. On the basis of this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued all medicines and started treatment with corticosteroids. Her respiratory condition and chest radiographic findings improved. The timing of administration and rechallenge with other drugs suggested that the herbal medicines were the causative drugs. The primary concern was Seisin-renshi-in, because it contains Ougon (skullcap; a known cause of pneumonitis) and because a drug lymphocyte stimulation test was positive for Seisin-renshi-in. This is the first report indicating that Seisin-renshi-in may cause diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage due to herbal medicines is a rare but emergent disorder. Therefore, treating physicians should be aware that it may be caused by herbal medicines, including Seisin-renshi-in.

We report a case of pneumonitis with alveolar hemorrhage induced by herbal medicines. A 73-year-old female was admitted to our hospital due to dyspnea and the presence of an abnormal shadow on the chest roentgenogram. She had received treatment with numerous drugs, including the following herbal medicines: Chest revealed diffuse ground-glass shadows in both lungs. The bronchoalveolar lavage fluid was progressively bloody. In addition, culture did not show the presence of microorganisms in the fluid. Moreover, there were no findings suggestive of rheumatic disease or vasculitides. Based on this evidence, we suspected drug-induced diffuse alveolar hemorrhage. She discontinued the use of all previous agents, and received treatment with corticosteroids. Her respiratory condition and the chest roentgenogram improved. According the a drug test was positive for Seisin-renshi-in. is the first report indicating that Seisin-renshi-in may cause diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage herbal medicines a rare but emergent disorder. Therefore, treating physicians should be aware that herbal medicines, including Seisin-renshi-in, may cause diffuse alveolar hemorrhage.

There are a number of suggested predictive factors of nivolumab for non-small cell lung cancer (NSCLC), however, there is not enough evidence to determine a single factor that can predict the efficacy of nivolumab. As the progress of biomarkers for cancer treatment is improving, it has been speculated that certain clinical factors serve an important role when predicting the outcome of chemotherapy. A total of 67 patients treated with nivolumab for NSCLC from 2016-2017 were prospectively investigated. Age, sex, the Eastern Cooperative Oncology Group Performance Status, histology, epidermal growth factor receptor (EGFR) mutation, history of chemotherapy, smoking status, use of statins, use of fibrates, use of dipeptidyl peptidase-4 (DPP-4) inhibitors, and use of metformin were examined as clinical factors. Statistical analyses were performed using the Kaplan-Meier method and Cox regression adjusted for risk factors and the tumor response of 67 patients was assessed. The patients had a median age of 67 years (range, 36-87 years), and 46 males and 21 females were enrolled; performance status 0/1 was 59. Cases were categorized as adenocarcinoma (n=41), squamous cell carcinoma (n=17) and other (n=9). A total of 13 patients (19.4%) had EGFR mutations. These clinical factors were not statistically significant in overall survival (OS). Clinical laboratory findings, complications and use of medical agents including antidiabetes mellitus or lipidemia were also analyzed. Statins exhibited statistical significance for response (P=0.02). Time-to-treatment failure (TTF) in statin-use group was not reached [95% confidence interval (CI): 1.9-not reached] and was 4.0 months (95% CI: 2.0-5.4) in the non-statin group (P=0.039). The median OS in statin-use group was not reached (95% CI: 8.7-not reached) and was 16.5 months (95% CI: 7.5-not reached) in the non-statin group (P=0.058). NSCI patients previously treated with nivolumab who were administered statins exhibited an increased response rate and longer TTF. This response was not statistically significant in OS.

No target therapies are presently available in the treatment of small-cell lung cancer of Lung (SCLC). Therefore, there is a need to develop new therapeutic agents. The protein kinases are a family of genes that play critical roles in various signaling pathways. Some cancer cells show addiction to constitutive activation of certain signaling pathways for proliferation and survival. To identify new drug targets for SCLC, we screened a panel of small interfering RNAs (siRNAs) that target 720 genes encoding human protein kinases and related proteins using SBC5 SCLC cell. Polo-like kinase (PLK1) inhibition suppressed cell proliferation strongest among 20 significant promising total genes using different 5 SCLC cells as a varidation study). PLK1 mRNA expression was significantly higher than other pathological phenotypes among 20 celllines and the 200 clinical samples consist of three independent cohorts. The patients with high PLK1 expresssion was significantly associated with poor prognosis in SCLC patients. Furthermore we investigated the SN 38 and VP-16 had synergistic effect with PLK inhibition via dual PLK1 inhibition. Our results indicated that PLK1 inhibitor as BI 2536 and Volasertib, was a promising molecular target therapy for pharmacologic intervention in SCLC in both monotherapy and the combination therapy with SN38 and VP-16.

Crizotinib, a multi-targeted tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) and c-MET, has shown significant anti-tumor activity in gene-rearranged non-small cell lung cancer. Esophagitis associated with crizotinib treatment is not currently recognized as common adverse event. Here, we present a case of crizotinib-induced severe ulcerative esophagitis 3 years after chemoradiotherapy. The patient was a 30-year-old man who was diagnosed as having primary adenocarcinoma of the lung. He received chemotherapy (biweekly cisplatin plus docetaxel) and thoracic radiotherapy (60 Gy) concurrently. Maintenance therapy with pemetrexed was added after completion of the chemoradiotherapy. About 3 years later, lung cancer recurred at the primary site, with bone metastasis. The ALK protein was detected by immunohistochemistry. Therefore, crizotinib treatment was initiated as second-line therapy. After 1 week, the patient complained of odynophagia and dysphagia. Thirteen days after the initiation of crizotinib, esophagogastroduodenoscopy showed a severe ulcer in the middle portion of the esophagus. Crizotinib was discontinued immediately. Follow-up esophagogastroduodenoscopy 1 week later showed a slight esophageal stenosis with an ulcer scar 24–28 cm distant from the incisors. Clinicians need to be aware that crizotinib may lead to severe esophagitis and that thoracic radiotherapy might worsen esophagitis.