Takuro Mizukami

MEK inhibitor for gastric cancer with MEK1 gene mutations

The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors. Mol Cancer Ther; 13(12); 3098–106. ©2014 AACR.

An activating ALK gene mutation in ALK IHC-positive/FISH-negative nonsmall-cell lung cancer

ABSTRACT The detection of ALK rearrangements is mainly performed using fluorescence in-situ hybridization (FISH). However, such analyses can yield false-positive and false-negative results. Other ALK diagnostic techniques have been developed, including immunohistochemistry (IHC) for the detection of the chimeric ALK protein and a reverse transcriptase-polymerase chain reaction analysis to search for the presence of abnormal fusion transcript. Some studies have reported significant clinical improvement after treatment with crizotinib in patients with tumors that were designated as ALK-negative by FISH but were found to be ALK-positive by IHC. In the present study, we identified an ALK R1192G mutation in an NSCLC clinical sample with ALK IHC-positive/FISH-negative findings and showed that this mutation was an oncogenic activating mutation. In addition, ALK inhibitors were likely to be effective against NSCLC cells carrying this mutation. To the best of our knowledge, this is the first study to show that a clinical sample with ALK IHC-positive/FISH-negative findings has an ALK activating mutation. Although this patient has not been treated with any ALK inhibitors because of no recurrence, ALK inhibitors can be effective against such NSCLC cells. To ensure that candidates for treatment with ALK inhibitors are not missed, further comprehensive analyses, such as next generation sequencing, should be introduced into clinical practice.

Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies

Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti‐EGFR therapies. In clinical samples, an FGF9 copy number gain of >5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild‐type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti‐EGFR therapies but was observed in one sample from the seven non‐responders with wild‐type KRAS, and two samples from non‐responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9‐amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9‐overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti‐EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti‐EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti‐FGFR inhibitor. These findings strongly encourage the development of FGFR‐targeted therapy for CRC patients with FGF9 gene upregulation.

EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition

Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEK1 gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1‑mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.

Early morphological change for predicting outcome in metastatic colorectal cancer after regorafenib

Background and Objective It is unclear whether early morphological change (EMC) is a predictive marker for regorafenib in metastatic colorectal cancer (mCRC). Therefore, the present study investigated whether EMC can predict the outcome of mCRC patients receiving regorafenib. Results This study evaluated 68 patients. Among 52 patients with lung metastasis, 16 (31%) had cavity formation (CF). The median progression-free survival (PFS) and overall survival (OS) in patients with/without CF were 4.2/2.4 months (p<0.01) and 9.2/6.5 months (p=0.09), respectively. Among 45 patients with liver metastasis, 14 (31%) had active morphological response (MR). The median PFS and OS in patients with/without active MR were 5.3/2.4 months (p<0.01) and 13.6/6.9 months (p=0.02), respectively. Overall, 25 patients (37%) had EMC. The median PFS and OS in patients with/without EMC were 5.3/2.1 months (p<0.01) and 13.3/6.1 months (p<0.01), respectively. Materials and Methods This retrospective study included mCRC patients with lung and/or liver metastases receiving regorafenib. CF in lung metastasis and MR in liver metastasis were evaluated at the first post-treatment computed tomography scan. EMC was determined as CF and/or active MR. We compared PFS and OS between patients with and those without EMC. Conclusions EMC could be a useful predictive marker for regorafenib in mCRC.

Profile of trifluridine/tipiracil hydrochloride in the treatment of metastatic colorectal cancer: efficacy, safety, and place in therapy

TAS-102, with its robust survival efficacy and feasible toxicity, is one of the standard salvage-line treatments for patients with metastatic colorectal cancer (mCRC). No definitive data are available to determine which drug should be administered first during salvage-line treatment. Therefore, it is imperative that we establish the sequence of administration by considering drug toxicity profiles based on patient characteristics, such as age, performance status, comorbidities, tolerability to previous treatments, and patient preferences. The identification of predictive biomarkers in response to TAS-102 or its toxicity is urgently needed for better patient selection. Moreover, to strengthen efficacy or relieve toxicity, combinations with other agents, which could potentially emerge as standard treatment regimens, have been investigated and compared to existing active regimens for mCRC.

Clinicopathological and genetic differences between low‐grade and high‐grade colorectal mucinous adenocarcinomas

Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high‐grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low‐grade mucinous adenocarcinoma (low‐MC) and high‐grade mucinous adenocarcinoma (high‐MC).

Identification of a FGFR3-TACC3 fusion in esophageal cancer

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Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan

Background Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients. Patients and methods The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome. Results Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1–60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy. Conclusion Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully.