The association between ERK inhibitor sensitivity and molecular characteristics in colorectal cancer.

The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.

Amyloid precursor protein and its phosphorylated form in non-small cell lung carcinoma.

Amyloid precursor protein (APP) is a well-known to be involved in the development of Alzheimer's disease and harbors several phosphorylation sites in its cytoplasmic domain. APP has been also proposed as one of the molecules involved in cell proliferation and invasion in several human malignancies. However, the roles of APP including its phosphorylated form (p-APP) have remained largely unexplored in non-small cell lung carcinoma (NSCLC). Therefore, in this study, we first examined both APP and p-APP expressions and then explored the association between p-APP/APP status and clicopathological parameters in NSCLC. The number of APP-positive cases was 24/91 (26%) in adenocarcinomas (Ad) and 16/35 (46%) in squamous cell carcinomas (Sq), respectively. p-APP-positive cases in Ad and Sq were 28 (31%) and 17 (49%), respectively. In Ad cases, both APP and p-APP were significantly associated with clinical stages (APP and p-APP), pathologic T (p-APP), and pathologic N (APP and p-APP) of the cases examined. In Sq cases, there were no significant associations between APP status and any of the clinicopathological parameters examined with an exception of the significant correlation of p-APP with lymphatic invasion. APP status was not significantly associated with overall survival (OS) of Ad patients but a significant association was detected between p-APP-positive cases and OS of these patients (p < 0.0001). In Sq cases, both APP- (p = 0.01) and p-APP-positive (p = 0.04) groups were also significantly associated with adverse clinical outcome. These results did firstly demonstrate that APP, in particular, p-APP, is considered a potent prognostic factor for both Ad and Sq lung carcinoma patients. However, APP signaling including its phosphorylation signal are considered different between these two types of NSCC cells and further investigations are required for clarification.

Amyloid precursor protein in human breast cancer: an androgen-induced gene associated with cell proliferation.

Amyloid precursor protein (APP) is a transmembrane protein that is highly expressed in brain tissue. Recently, APP has been implicated in some human malignancies, and its regulation by androgens has also been demonstrated. Such findings suggest the importance of APP in hormone-dependent breast carcinoma, but APP has not yet been examined in breast carcinoma tissues. Therefore, in this study, we examined the biological and clinical significance of APP in breast carcinoma using immunohistochemistry and in vitro studies. APP immunoreactivity was detected in 57 out of 117 (49%) breast carcinoma tissues examined, and it was positively associated with androgen receptor (AR) expression. APP immunoreactivity was also significantly associated with Ki-67 LI and increased risk of recurrence in the estrogen receptor (ER)-positive cases, and was an independent prognostic factor in these patients. Subsequent in vitro experiments demonstrated that APP mRNA expression was significantly induced by biologically active androgen dihydrotestosterone in both a dose-dependent and a time-dependent manner in MCF-7 breast carcinoma cells, which was potently suppressed by an AR blocker hydroxyflutamide. Moreover, cell proliferation activity of MCF-7 and MDA-MB-231 cells was significantly associated with their APP expression level. These findings suggest that APP is an androgen-induced gene that promotes proliferation activity of breast carcinoma cells. Moreover, APP immunohistochemical status is considered a potent prognostic factor in ER-positive breast cancer patients.