The Hippo Signaling Pathway Manipulates Cellular Senescence.

The Hippo pathway, a kinase cascade, coordinates with many intracellular signals and mediates the regulation of the activities of various downstream transcription factors and their coactivators to maintain homeostasis. Therefore, the aberrant activation of the Hippo pathway and its associated molecules imposes significant stress on tissues and cells, leading to cancer, immune disorders, and a number of diseases. Cellular senescence, the mechanism by which cells counteract stress, prevents cells from unnecessary damage and leads to sustained cell cycle arrest.

Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization.

KRAS-specific inhibitors have shown promising antitumor effects, especially in non-small cell lung cancer, but limited efficacy in colorectal cancer (CRC) patients. Recent studies have shown that EGFR-mediated adaptive feedback mediates primary resistance to KRAS inhibitors, but the other resistance mechanisms have not been identified. In this study, we investigated intrinsic resistance mechanisms to KRAS inhibitors using patient-derived CRC cells (CRC-PDCs).

Prognosis and tumor microenvironment in pseudohypoxic pheochromocytoma/paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare tumors that occur in the adrenal medulla and extra-adrenal tissues, respectively. The prognosis and tumor microenvironment (TME) of pseudohypoxic PPGL as a major entity have not been fully described. Based on the clinical database of 65 patients with PPGL, we assessed the morphological features as well as the immunohistochemistry of pseudohypoxia-related proteins (SDHB and CAIX) and TME-related immune cell markers.

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.

Dynamics in the Prostate Immune Microenvironment Induced by Androgen Deprivation Therapy.

Background: The influence of testosterone on the prostate's immune microenvironment remains unclear. This study aims to elucidate the dynamics of immune cells in the prostate following androgen deprivation therapy (ADT).

Methods: We retrospectively compared prostate needle biopsy and radical prostatectomy specimens from 33 patients who underwent both procedures, along with neoadjuvant ADT at a single institution.

Sex differences in toxicities and survival outcomes among Japanese patients with Stage III colorectal cancer receiving adjuvant fluoropyrimidine monotherapy: A pooled analysis of 4 randomized controlled trials (JCOG2310A).

Background: Fluoropyrimidine remains the key agent of adjuvant chemotherapy for stage III colorectal cancer (CRC). Western studies have shown that female sex is a favorable prognostic factor after surgery, but it is also a risk factor for adverse events (AEs) during adjuvant chemotherapy with fluoropyrimidine. However, little is known about whether sex differences in treatment outcomes exist in this setting in the Asian population.

Methyl scanning approach for enhancing the biological activity of the linear peptidic natural product, efrapeptin C.

Efrapeptin C (1a) is a large peptidic natural product comprising a 15-mer linear sequence and exerts potent anticancer activity by inhibiting mitochondrial FF-ATP synthase. Residues 1-6 and 9-15 of 1a fold into two 3-helical domains and interact with ATP synthase, while the central β-Ala-7-Gly-8 region functions as a flexible linker of the two domains. To enhance the function of 1a by minimally modifying its structure, we envisioned attaching one small methyl group to the β-Ala-7-Gly-8 and designed six methylated analogues 1b-1g, differing only in the position and configuration of the methyl group.

Inhibition of ROS1 activity with lorlatinib reversibly suppresses fertility in male mice.

Background: Inhibition of sperm maturation in the epididymis is a promising post-testicular strategy for short-acting male contraceptives. It has been shown that ROS1, a receptor tyrosine kinase expressed in the epididymis, is essential for epididymal differentiation, sperm maturation, and male fertility in mice. However, it is unknown if inhibition of ROS1 suppresses male fertility reversibly.

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.

Metabolically inducing defects in DNA repair sensitizes -wild-type cancer cells to replication stress.

Metabolic reprogramming from oxidative respiration to glycolysis is generally considered to be advantageous for tumor initiation and progression. However, we found that breast cancer cells forced to perform glycolysis acquired a vulnerability to PARP inhibitors. Small-molecule inhibition of mitochondrial respiration-using glyceollin I, metformin, or phenformin-induced overproduction of the oncometabolite lactate, which acidified the extracellular milieu and repressed the expression of homologous recombination (HR)-associated DNA repair genes.

Different efficacy of tyrosine kinase inhibitors by KIT and PGFRA mutations identified in circulating tumor DNA for the treatment of refractory gastrointestinal stromal tumors.

Background: While advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST.

Methods: We conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients.

Severe Thrombocytopenia from Trastuzumab and Pertuzumab Combination Therapy in a Patient with HER2-Positive Metastatic Rectal Cancer.

Introduction: In recent years, trastuzumab and pertuzumab have been used in treatment protocols for patients with HER2-positive colorectal cancer. Although severe thrombocytopenia is an uncommon side effect of anti-HER2 antibody therapy, we present the first patient with HER2-positive metastatic rectal cancer who developed significant thrombocytopenia after trastuzumab and pertuzumab administration.

Case Presentation: The condition was identified as drug-induced immune thrombocytopenia associated with trastuzumab and pertuzumab.

Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer.

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK-TKIs) via emergence of a subpopulation of drug-tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib-induced DTP cells from a patient-derived ALK non-small-cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol).

Loss of phosphatase and tensin homolog expression castration-sensitive prostate cancer predicts outcomes in men after prostatectomy.

Objectives: This study aimed to investigate the potential for using the phosphatase and tensin homolog (PTEN) gene as a prognostic marker in post-prostatectomy patients with castration-sensitive prostate cancer (PCa).

Methods: A total of 180 patients with castration-sensitive PCa who underwent radical prostatectomy at our institution were included in this study. PTEN expression was evaluated using immunohistochemistry, and patients were classified into two groups based on the staining intensity: PTEN-Normal and PTEN-Loss.

ctDNA-based molecular residual disease and survival in resectable colorectal cancer.

The interim analysis of the CIRCULATE-Japan GALAXY observational study demonstrated the association of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection with recurrence risk and benefit from adjuvant chemotherapy (ACT) in resectable colorectal cancer (CRC). This updated analysis with a 23-month median follow-up, including 2,240 patients with stage II-III colon cancer or stage IV CRC, reinforces the prognostic value of ctDNA positivity during the MRD window with significantly inferior disease-free survival (DFS; hazard ratio (HR): 11.99, P < 0.

Inverse Correlation between -Carrying Abundance in Colorectal Cancer Liver Metastases and the Number of Organs Involved in Recurrence.

Colibactin, a genotoxin produced by strains harboring the polyketide synthetase () gene cluster, causes DNA damage and somatic mutations. is enriched in primary colorectal cancer (CRC) and is associated with clonal driver mutations, but its role in CRC liver metastasis is unclear. We assessed the association of in CRC liver metastasis tissues with systemic and local immune responses and the number of organs involved in recurrence using specimens and clinicopathological data from 239 patients with CRC liver metastasis who underwent metastasectomy.

Real-world treatment costs of first-line treatment for metastatic colorectal cancer: a survey of the JCOG colorectal cancer study group.

Background: Although treatment outcomes for metastatic colorectal cancer (mCRC) have dramatically improved over the past few decades, drug costs have also significantly increased. This study aimed to investigate which first-line treatment regimens for mCRC are actually used (frequency) in Japanese practice and at what cost.

Methods: We collected data on patients with mCRC who received first-line treatment at 37 institutions of the Japan Clinical Oncology Group Colorectal Cancer Study Group from July 2021 to June 2022, and calculated the cost of regimens.

Exploratory Study Identifies Matrix Metalloproteinase-14 and -9 as Potential Biomarkers of Regorafenib Efficacy in Metastatic Colorectal Cancer.

In identifying biomarkers for anticancer drugs, the lack of objectivity in selecting candidate factors makes interpretation difficult. We performed preclinical analysis and a translational validation study to identify candidate biomarkers for regorafenib efficacy in metastatic colorectal cancer (mCRC). Using in silico COMPARE analysis with a human cancer cell line panel, JFCR39, we selected candidate biomarkers whose expression correlates with regorafenib sensitivity.