Frequent copy number gain of MCL1 is a therapeutic target for osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor primarily affecting children and adolescents. The lack of progress in drug development for OS is partly due to unidentified actionable oncogenic drivers common to OS. In this study, we demonstrate that copy number gains of MCL1 frequently occur in OS, leading to vulnerability to therapies based on Mcl-1 inhibitors.

Identification of C-mannosylation in a receptor tyrosine kinase AXL.

C-mannosylation is a unique type of glycosylation in which a mannose is added to tryptophan in a protein. However, the biological function of C-mannosylation is still largely unknown. AXL is a receptor tyrosine kinase, and its overexpression contributes to tumor malignancy.

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer.

Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK + NSCLC) patient-derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth.

Promoting biological similarity by collagen microfibers in 3D colorectal cancer-stromal tissue: Replicating mechanical properties and cancer stem cell markers.

The extracellular matrix (ECM) of cancer tissues is rich in dense collagen, contributing to the stiffening of these tissues. Increased stiffness has been reported to promote cancer cell proliferation, invasion, metastasis, and prevent drug delivery. Replicating the structure and mechanical properties of cancer tissue in vitro is essential for developing cancer treatment drugs that target these properties.

3D layered co-culture model enhances Trastuzumab Deruxtecan sensitivity and reveals the combined effect with G007-LK in HER2-positive non-small cell lung cancer.

Human epidermal growth factor receptor 2 (HER2) aberrations are observed in various cancers. In non-small cell lung cancer, genetic alterations activating HER2, mostly exon 20 insertion mutations, occur in approximately 2-4% of cases. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate has been approved as the first HER2-targeted drug for HER2-mutant lung cancer.

descSPIM: an affordable and easy-to-build light-sheet microscope optimized for tissue clearing techniques.

Despite widespread adoption of tissue clearing techniques in recent years, poor access to suitable light-sheet fluorescence microscopes remains a major obstacle for biomedical end-users. Here, we present descSPIM (desktop-equipped SPIM for cleared specimens), a low-cost ($20,000-50,000), low-expertise (one-day installation by a non-expert), yet practical do-it-yourself light-sheet microscope as a solution for this bottleneck. Even the most fundamental configuration of descSPIM enables multi-color imaging of whole mouse brains and a cancer cell line-derived xenograft tumor mass for the visualization of neurocircuitry, assessment of drug distribution, and pathological examination by false-colored hematoxylin and eosin staining in a three-dimensional manner.

In vitro throughput screening of anticancer drugs using patient-derived cell lines cultured on vascularized three-dimensional stromal tissues.

The development of high-throughput anticancer drug screening methods using patient-derived cancer cell (PDC) lines that maintain their original characteristics in an in vitro three-dimensional (3D) culture system poses a significant challenge to achieving personalized cancer medicine. Because stromal tissue plays a critical role in the composition and maintenance of the cancer microenvironment, in vitro 3D-culture using reconstructed stromal tissues has attracted considerable attention. Here, a simple and unique in vitro 3D-culture method using heparin and collagen together with fibroblasts and endothelial cells to fabricate vascularized 3D-stromal tissues for in vitro culture of PDCs is reported.

BET protein-dependent E2F pathway activity confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer.

WNT/β-catenin signaling is aberrantly activated in colorectal cancer (CRC) mainly by loss-of-function mutations in adenomatous polyposis coli (APC) and is involved in tumor progression. Tankyrase inhibitors, which suppress WNT/β-catenin signaling, are currently in pre-clinical and clinical trials. However, the mechanisms of resistance to tankyrase inhibitors remain unclear.

APC/PIK3CA mutations and β-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells.

Background: Aberrant WNT/β-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, β-catenin repressors. Tankyrase inhibitors block WNT/β-catenin signaling and colorectal cancer (CRC) growth.

Ultra-Rapid and Specific Gelation of Collagen Molecules for Transparent and Tough Gels by Transition Metal Complexation.

Collagen is the most abundant protein in the human body and one of the main components of stromal tissues in tumors which have a high elastic modulus of over 50 kPa. Although collagen has been widely used as a cell culture scaffold for cancer cells, there have been limitations when attempting to fabricate a tough collagen gel with cells like a cancer stroma. Here, rapid gelation of a collagen solution within a few minutes by transition metal complexation is demonstrated.

Brigatinib in Japanese patients with ALK-positive non-small-cell lung cancer: Final results of the phase 2 J-ALTA trial.

The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC.

Spatiotemporal commonality of the TCR repertoire in a T-cell memory murine model and in metastatic human colorectal cancer.

Immune checkpoint inhibitors (ICIs) have shown superior clinical responses and significantly prolong overall survival (OS) for many types of cancer. However, some patients exhibit long-term OS, whereas others do not respond to ICI therapy at all. To develop more effective and long-lasting ICI therapy, understanding the host immune response to tumors and the development of biomarkers are imperative.

C-terminus of serine-arginine protein kinase-like protein, SrpkF, is involved in conidiophore formation and hyphal growth under salt stress in Aspergillus aculeatus.

The serine-arginine protein kinase-like protein, SrpkF, was identified as a regulator for the cellulose-responsive induction of cellulase genes in Aspergillus aculeatus. To analyze various aspects of SrpkF function, we examined the growth of the control strain (MR12); C-terminus deletion mutant, which produced SrpkF (ΔCsrpkF); whole gene-deletion mutant of srpkF (ΔsrpkF), srpkF overexpressing strain (OEsprkF); and the complemented strain (srpkF) under various stress conditions. All test strains grew normally on minimal medium under control, high salt (1.

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer.

The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib (a first-generation ALK-TKI)-refractory ALK-rearranged NSCLC.

Acquired resistance to BRAF inhibitors is mediated by BRAF splicing variants in BRAF V600E mutation-positive colorectal neuroendocrine carcinoma.

Neuroendocrine carcinomas (NECs), a poorly differentiated subtype of neuroendocrine neoplasms, are aggressive and have a poor prognosis. Colorectal neuroendocrine carcinomas (CRC-NECs) are observed in about 0.6% of all patients with CRC.

Sensitivity to dabrafenib and trametinib treatments in patients with non-small-cell cancer harboring BRAF compound mutations: A pooled analysis of BRAF p.V600E-positive advanced non-small-cell lung cancer.

Purpose: The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation.

Methods: We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer.

Systematic identification of ALK substrates by integrated phosphoproteome and interactome analysis.

The sensitivity of phosphorylation site identification by mass spectrometry has improved markedly. However, the lack of kinase-substrate relationship (KSR) data hinders the improvement of the range and accuracy of kinase activity prediction. In this study, we aimed to develop a method for acquiring systematic KSR data on anaplastic lymphoma kinase (ALK) using mass spectrometry and to apply this method to the prediction of kinase activity.