Final overall survival analysis from the phase III J-ALEX study of alectinib versus crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive non-small-cell lung cancer.

BACKGROUND: Mature progression-free survival (PFS) data from the phase III J-ALEX study showed superiority for alectinib versus crizotinib [hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.26-0.52; median PFS 34.1 versus 10.2 months, respectively] in advanced ALK (anaplastic lymphoma kinase)-positive non-small-cell lung cancer (NSCLC). Overall survival (OS) data were immature (HR 0.80, 99.8799% CI 0.35-1.82) at the time of data cut-off (30 June 2018). We report final OS data after ≥5 years of follow-up. PATIENTS AND METHODS: ALK inhibitor naive Japanese patients who were chemotherapy naive or had received one prior chemotherapy regimen were enrolled. Patients were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was independent review facility-assessed PFS, with OS (not fully powered) as a secondary endpoint. RESULTS: Median duration of OS follow-up was 68.6 months with alectinib and 68.0 months with crizotinib. Treatment with alectinib did not prolong OS relative to crizotinib (HR 1.03, 95.0405% CI 0.67-1.58; P = 0.9105). Five-year OS rates were 60.9% (95% CI 51.4-70.3) with alectinib and 64.1% (95% CI 54.9-73.4) with crizotinib. In total, 91.3% (n = 95/104) of crizotinib-treated patients and 46.6% (n = 48/103) of alectinib-treated patients received at least one subsequent anticancer therapy. After study drug discontinuation, 78.8% of patients in the crizotinib arm switched to alectinib, while 10.7% of patients in the alectinib arm switched to crizotinib as a first subsequent anticancer therapy. Patients randomized to crizotinib tended to switch treatment earlier than those randomized to alectinib. CONCLUSION: Final OS analysis from J-ALEX did not show superiority of alectinib to crizotinib; this result was most likely confounded by treatment crossover. Alectinib remains a standard of care for the treatment of patients with advanced ALK-positive NSCLC.

Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

Real-world prevalence of programmed death ligand 1 expression in locally advanced or metastatic non-small-cell lung cancer: The global, multicenter EXPRESS study.

OBJECTIVES: Tumor programmed death ligand 1 (PD-L1) expression is associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicenter, retrospective observational study to determine real-world prevalence of tumor PD-L1 expression in patients with NSCLC. MATERIALS AND METHODS: Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumor tissue block (≤5 years old) obtained before treatment were identified in 45 centers across 18 countries. Tumor samples from eligible patients were selected consecutively, when possible. PD-L1 expression was evaluated at each center using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). RESULTS: Of 2617 patients who met inclusion criteria, 2368 (90%) had PD-L1 data; 530 (22%) patients had PD-L1 TPS ≥ 50%, 1232 (52%) had PD-L1 TPS ≥ 1%, and 1136 (48%) had PD-L1 TPS < 1%. The most common reason for not having PD-L1 data (n = 249) was insufficient tumor cells (<100) on the slide (n = 170 [6%]). Percentages of patients with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively were: 22%/52% in Europe; 22%/53% in Asia Pacific; 21%/47% in the Americas, and 24%/55% in other countries. Prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports from metastatic NSCLC studies. Among 1064 patients negative for both EGFR mutation and ALK alteration, the percentage with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively, were 27% and 53%. CONCLUSIONS: This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumor expression using the 22C3 pharmDx kit. Testing failure rate was low with local evaluation of PD-L1 TPS across a large number of centers. Prevalence of PD-L1 TPS ≥ 50% and TPS ≥ 1% among patients with stage IIIB/IV NSCLC was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations.

Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study.

BACKGROUND: Atezolizumab (anti-programmed death-ligand 1 [PD-L1]) received approval from the US Food and Drug Administration and European Medicines Agency for previously treated advanced non-small-cell lung cancer based on OAK-a randomised, phase III trial that showed significantly improved survival with atezolizumab versus docetaxel regardless of PD-L1 expression. With longer follow-up, we summarised the characteristics of long-term survivors (LTSs). METHODS: In OAK (NCT02008227), patients were randomised 1:1 to receive atezolizumab or docetaxel until loss of clinical benefit or disease progression, respectively. Overall survival was evaluated after a 26-month minimum follow-up, including in patient subgroups defined by best overall response (BOR). LTSs were defined as patients who lived ≥24 months since randomisation. Non-LTSs died within 24 months, and patients censored before 24 months were excluded from the analysis. The baseline characteristics, including biomarkers, BOR, subsequent non-protocol therapy (NPT) and safety, are reported. RESULTS: Survival benefit with atezolizumab was observed across all patient subgroups defined by BOR. More atezolizumab-treated patients were LTSs versus those treated with docetaxel (28% versus 18%). Most atezolizumab responders were LTSs (77%) versus only 48% of docetaxel responders. However, 21% of atezolizumab-arm LTSs had progressive disease (PD) as BOR, and more atezolizumab-arm LTSs than non-LTSs continued treatment post-PD. Fifty-two percent of docetaxel-arm LTSs received immunotherapy as subsequent NPT. Despite extended treatment duration in atezolizumab-arm LTSs (median, 18 months), atezolizumab was well tolerated. CONCLUSIONS: After >2 years of follow-up, atezolizumab continued to provide durable survival benefit versus docetaxel, with tolerable safety. Atezolizumab-arm LTSs were enriched for patients with high PD-L1 expression and included PD-L1-negative patients. Long-term survival was not limited to responders.

Light compensation points in shade-grown seedlings of deciduous broadleaf tree species with different successional traits raised under elevated CO2.

We measured leaf photosynthetic traits in shade-grown seedlings of four tree species native to northern Japan, raised under an elevated CO2 condition, to investigate the effects of elevated CO2 on shade tolerance of deciduous broadleaf tree species with different successional traits. We considered Betula platyphylla var. japonica and Betula maximowicziana as pioneer species, Quercus mongolica var. crispula as a mid-successional species, and Acer mono as a climax species. The plants were grown under shade conditions (10% of full sunlight) in a CO2 -regulated phytotron. Light compensation points (LCPs) decreased in all tree species when grown under elevated CO2 (720 µmol·mol(-1) ), which were accompanied by higher apparent quantum yields but no photosynthetic down-regulation. LCPs in Q. mongolica and A. mono grown under elevated CO2 were lower than those in the two pioneer birch species. The LCP in Q. mongolica seedlings was not different from that of A. mono in each CO2 treatment. However, lower dark respiration rates were observed in A. mono than in Q. mongolica, suggesting higher shade tolerance in A. mono as a climax species in relation to carbon loss at night. Thus, elevated CO2 may have enhanced shade tolerance by lowering LCPs in all species, but the ranking of shade tolerance related to successional traits did not change among species under elevated CO2 , i.e. the highest shade tolerance was observed in the climax species (A. mono), followed by a gap-dependent species (Q. mongolica), while lower shade tolerance was observed in the pioneer species (B. platyphylla and B. maximowicziana).

Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study).

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. PATIENTS AND METHODS: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. RESULT: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. CONCLUSIONS: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. REGISTRATION NUMBER: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).

Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.

BACKGROUND: HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied dacomitinib in patients with HER2-mutant or amplified lung cancers. PATIENTS AND METHODS: As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral dacomitinib at 30-45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity. RESULTS: We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of dacomitinib (95% CI 7-21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of dacomitinib with mirtazapine. CONCLUSIONS: Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers. CLINICALTRIALSGOV: NCT00818441.

Detectability of hepatocellular carcinoma on gadoxetic acid-enhanced MRI at 3 T in patients with severe liver dysfunction: clinical impact of dual-source parallel radiofrequency excitation.

AIM: To clarify the detectability of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI at 3 T with dual-source parallel radiofrequency (RF) excitation. MATERIALS AND METHODS: Twelve patients with 26 HCCs who each underwent multidetector row CT (MDCT), gadoxetic acid-enhanced MRI with dual-source parallel RF excitation, and angiography-assisted CT prior to living related-liver transplantation. Three blinded readers independently reviewed the images obtained by each imaging technique for the presence of HCC on a segment-by-segment basis using a five-point confidence scale. The area under the receiver operating characteristic curve (Az), sensitivity, and specificity were compared among the three techniques. RESULTS: The Az values of gadoxetic acid-enhanced MRI were highest for all readers, although no significant difference in Az value among the three methods was obtained. No significant differences in sensitivity or specificity were observed among the three techniques for each reader. CONCLUSION: Gadoxetic acid-enhanced MRI at 3 T with dual-source parallel RF excitation has relatively high-level diagnostic potential for the detection of HCC in patients with severe liver dysfunction, which was equivalent to that of MDCT and angiography-assisted CT. Dual-source parallel RF excitation would have a clinical impact on 3 T MRI of the liver.

LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade.

Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)-Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.

Time to first cigarette and lung cancer risk in Japan.

BACKGROUND: Cigarette smoking is the major cause of lung cancer (LC). Although the time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, little information is available on its possible relation to LC. PATIENTS AND METHODS: This case-control study includes a total of 1572 incident LC cases and 1572 non-cancer controls visiting for the first time the Aichi Cancer Center Hospital between 2001 and 2005. We estimated the odds ratio (OR) and 95% confidence interval (CI) for TTFC using a logistic regression model after adjustment for several potential confounders. RESULTS: TTFC was inversely associated with the risk of LC. This association was consistent across histological subtypes of LC. For all LCs considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC >60 min, the adjusted ORs were 1.08 (95% CI, 0.73-1.61) for TTFC of 31-60 min, 1.40 (0.98-2.01) for 6-30 min and 1.86 (1.28-2.71) for within 5 min (Ptrend, < 0.001). Statistically marginally significant heterogeneity by histological subtype was observed (Pheterogeneity, 0.002). CONCLUSIONS: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of LC and is therefore an independent marker of exposure to tobacco smoking.

Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells.

Malignant pleural mesothelioma (MPM) is resistant to chemotherapy and thus shows a dismal prognosis. Osteopontin (OPN), a secreted noncollagenous and phosphoprotein, is suggested to be involved in the pathogenesis of MPM. However, the precise role of OPN, especially in the multidrug resistance of MPM, remains to be elucidated. We therefore established stable transfectants (ACC-MESO-1/OPN), which constitutively express OPN, to determine its role in the chemoresistance observed in MPM. The introduction of the OPN gene provides MPM cells with upregulated multidrug resistance through the mechanism of enhanced hyaluronate (HA) binding. The expression of CD44 variant isoforms, which inhibit HA binding, significantly decreased in ACC-MESO-1/OPN cells in comparison to control transfectants. Interestingly, the inhibition of the HA-CD44 interaction abrogated multidrug resistance in the ACC-MESO-1/OPN, thus suggesting the involvement of the surviving signal emanating from the HA-CD44 interaction. An enhanced level of the p-Akt in ACC-MESO-1/OPN cells was observed, and was diminished by CD44 siRNA. Inhibition of the Akt phosphorylation increased in number of the cells underwent apoptosis induced by NVB, VP-16 and GEM. Collectively, these results indicate that OPN is strongly involved in multidrug resistance by enhancing the CD44 binding to HA.

A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy.

BACKGROUND: This is a randomized, double-blind, dose-ranging study in patients receiving highly emetogenic chemotherapy (HEC) to evaluate the safety, efficacy, and pharmacokinetics of palonosetron, in combination with dexamethasone. MATERIALS AND METHODS: We randomized 233 patients to receive palonosetron as a single i.v. bolus dose of 0.075, 0.25, or 0.75 mg before administration of HEC. Dexamethasone (12-16 mg i.v. on day 1, 8 mg i.v. on day 2, and 4-8 mg i.v. on day 3) was administered for prophylactic antiemesis. Pharmacokinetics of palonosetron was analyzed in 24 patients. RESULTS: In this study, all patients were given > or =50 mg/m(2) cisplatin, which was considered to be HEC. No significant differences in complete response (CR: no emesis and no rescue medication) rates were found in the first 24 h between the 0.075-, 0.25-, and 0.75-mg groups (77.6%, 81.8%, and 79.5%, respectively). In the 120-h period of overall observation, CR rates increased in a dose-dependent manner. In the 0.75-mg group, we observed a significantly longer time to treatment failure than in the 0.075-mg group (median time >120 versus 82.0 h, P = 0.038). Palonosetron was tolerated well and did not show any dose-related increase in adverse effects. CONCLUSIONS: Palonosetron at doses of 0.25 and 0.75 mg was shown to be effective in preventing chemotherapy-induced nausea and vomiting with high CR rates of patients treated with HEC in Japan. All tested doses of palonosetron were tolerated well.

Cytokine induction by a linear 1,3-glucan, curdlan-oligo, in mouse leukocytes in vitro.

OBJECTIVE: Curdlan, an extracellular bacterial polysaccharide, is a linear beta-1,3-glucan. Previously, we developed Curdlan-oligo (CRDO). We investigated its effect on the production of cytokines in leukocytes from mice, and compared its activity with that of SCG, a 6-branched 1,3-beta-glucan. METHODS: Splenocytes from DBA/2 mice were cultured with CRDO or SCG (0, 1, 10 or 100 microg/ml) in vitro, and then the supernatants were collected to measure cytokines. Bone marrow-derived dendritic cells (BMDCs) were cultured with CRDO (0, 1, 10 or 100 ng/ml) in vitro, and then the supernatant was collected to measure cytokines. RESULTS: SCG stimulated splenocytes in DBA/2 mice to produce GM-CSF, IFN-gamma and TNF-alpha. CRDO induced production of GM-CSF and IFN-gamma, but not TNF-alpha. The amounts of GM-CSF and IFN-gamma were small compared with those produced in response to SCG. The effect of SCG on TNF-alpha production was partially inhibited by CRDO. In bone marrow-derived dendritic cells, CRDO induced production of TNF-alpha and IL-6. CONCLUSION: Taken together, these results suggest that CRDO stimulated mouse leukocytes to induce the production of cytokines, and the mechanism of the effect of CRDO on leukocytes is different from that of SCG.

Immunosuppressive effect of ER-38925, a retinoic acid receptor subtype α-selective agonist, in mouse models of human graft-vs-host disease.

Graft-vs-host disease (GVHD) is a devastating disorder that determines the prognosis of patients who receive a bone marrow transplant. GVHD is caused by donor cells responding to host disparate MHC alleles. In this report, we demonstrate that ER-38925, a newly discovered retinoid agonist with selectivity to retinoic acid receptor subtype α (RAR-α), is a potent immunosuppressive agent in mouse models of human GVHD. In a mouse model of lethal acute GVHD (aGVHD), ER-38925 prolonged the lifespan of the recipient mice in a dose-dependent manner. Its effect at 1 mg/kg was almost comparable to that of cyclosporin A at 30 mg/kg. ER-38925 profoundly prevented the development of antiallogeneic cytotoxic T lymphocyte (CTL) response in the mouse model of aGVHD at 0.1 and 0.3 mg/kg. It strongly inhibited in vitro proliferation of alloantigenstimulated donor T lymphocytes, and RAR-α seemed to play an exclusive role in this effect since inhibition by all-trans retinoic acid, which can activate all subtypes of RAR, was completely reversed by an RAR-α selective antagonist. Moreover, it significantly inhibited the elevation of serum IL-12 and IFN-γ and LPS-induced serum TNF-α elevation, all of which are known to be crucial disease-exacerbating factors in this model and human GVHD, in the mouse model of aGVHD. These results suggest that ER-38925 prevents the development of aGVHD through substantial inhibition of anti-allogeneic responses of donor T lymphocytes. In addition, in vivo administration of ER-38925 also blocked serum anti-DNA autoantibody production in a mouse model of human chronic GVHD. This is the first report to clearly show the remarkable immunosuppressive effects of an RAR-α selective agonist in mouse models of human GVHD. These findings may allow an RAR-αselective agonist like ER-38925 to serve as a novel therapy to prevent both acute and chronic types of human GVHD.

CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells.

We previously established a highly metastatic subline, LNM35, from the NCI-H460 lung cancer cell line, and demonstrated upregulation of a novel gene, CLCP1 (CUB, LCCL-homology, coagulation factor V/VIII homology domains protein), in LNM35 and lung cancer specimens. In this study, we focused on the potential roles of that gene in cancer metastasis. First, we established stable LNM35 RNAi clones, in which CLCP1 expression was suppressed by RNAi, and found that their motility was significantly reduced, although growth rates were not changed. Next, in vitro selection of a phage display library demonstrated that a phage clone displaying a peptide similar to a sequence within the Sema domain of semaphorin 4B (SEMA4B) interacted with LNM35. Immunoprecipitation experiments confirmed interaction of CLCP1 with SEMA4B, regulation of CLCP1 protein by ubiquitination and proteasome degradation enhanced in the presence of SEMA4B. These results are the first to indicate that CLCP1 plays a role in cell motility, whereas they also showed that at least one of its ligands is SEMA4B and that their interaction mediates proteasome degradation by CLCP1. Although the physiological role of the interaction between CLCP1 and SEMA4B remains to be investigated, this novel gene may become a target of therapy to inhibit metastasis of lung cancers.