pci-32765 and Skin-Neoplasms

IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and its inhibition suppresses melanoma cell proliferation. We hypothesize that ibrutinib has a direct antitumor effect in melanoma cell lines and that treatment of metastatic melanomas with ibrutinib induces antitumor responses.. We assessed the ibrutinib effect on melanoma cell proliferation, apoptosis, and motility. Patients with metastatic melanoma refractory to PD-1 and MAPK inhibitors (if BRAFV600-mutant) were treated with ibrutinib, 840 mg PO QD, as part of a phase II clinical trial (clinicaltrials.gov NCT02581930).. Melanoma cell lines frequently express ITK, YES1, and EGFR. Ibrutinib suppressed cell motility and proliferation in most cell lines. Eighteen patients (13 male; median age 63.5 years, range 37-82; 12 with ipilimumab resistance) were enrolled. The most frequent side effects were fatigue (61%), anorexia (50%), hyponatremia (28%), nausea, and vomiting (22% each). No antitumor responses were seen. At a median follow-up of 6 months (0.3-35.8 months), the median progression-free survival was 1.3 months (range 0.2-5.5 months). Fifteen patients were discontinued from the study due to progression, and 14 patients had died from metastatic melanoma. All archived tumors expressed ITK, 41% had no expression of p16 and PTEN, and 61% had absent tumor-infiltrating lymphocytes (TILs). Ibrutinib significantly suppressed proliferating (Ki67+) CD19+ peripheral blood mononuclear cells and had no significant effect on other lymphocyte subsets.. Ibrutinib did not induce any meaningful clinical benefit. ITK expression may not be clinically relevant. Treatment-refractory metastatic melanomas have other fundamental defects (i.e. absent PTEN and p16 expression, absent TILs) that may contribute to an adverse prognosis.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Female; Humans; Interleukin-2; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Piperidines; Skin Neoplasms

Here, we present a novel case of a patient with chronic lymphocytic leukemia (CLL) who received CTLA-4 and then PD-1 immune-checkpoint blockade (ICB) as treatment for concomitant metastatic melanoma. Whereas the metastatic melanoma was responsive to ICB, the CLL rapidly progressed (but responded to ICB cessation and ibrutinib). There were no new genetic mutational drivers to explain the altered clinical course. PD-1/PD-L1/PD-L2 and CTLA-4/CD80/CD86 expression was not increased in CLL B cells, CD8+ or CD4+ T-cell subsets, or monocytes. The patient's CLL B cells demonstrated strikingly prolonged in vitro survival during PD-1 blockade, which was not observed in samples taken before or after ICB, or with other patients. To our knowledge, a discordant clinical course to ICB coupled with these biological features has not been reported in a patient with dual malignancies.

Topics: Antineoplastic Agents; B7-H1 Antigen; CTLA-4 Antigen; Disease Progression; Humans; Immune Checkpoint Inhibitors; Leukemia, Lymphocytic, Chronic, B-Cell; Melanoma; Programmed Cell Death 1 Receptor; Skin Neoplasms

Topics: Adenine; Adverse Drug Reaction Reporting Systems; Humans; Pharmacovigilance; Piperidines; Skin Neoplasms; United States; United States Food and Drug Administration

A series of novel ibrutinib analogues was synthesized, and their proliferation inhibitory activities against various B lymphoma cell lines (DaudiB and Raji) and solid tumor cells (B16, CT26, HepG2 and 4T1) were evaluated. The most potent compound, YL7, exhibited strong antiproliferative activity in all cell lines, and its IC

Topics: Adenine; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mice; Molecular Structure; Piperidines; Skin Neoplasms; Structure-Activity Relationship

Topics: Adenine; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Humans; Leg; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Piperidines; Prednisone; Pyrazoles; Pyrimidines; Rituximab; Skin Neoplasms; Vincristine

Skin cancer is one of the most common malignancies in dermatology. Patient compliance and prognosis of skin cancer are poor. Ibrutinib, a Bruton's Tyrosine Kinase (BTK) inhibitor, is a new anticancer drug used to treat many cancers. Therefore, we aimed to explore the role of ibrutinib in the treatment of skin cancer.. Cell Counting Kit-8 (CCK8) and plate cloning assay were used to detect cell proliferation. Apoptosis was determined by flow cytometry. Western blotting analysis was used to analyze the expression of key proteins that regulated autophagy. Proliferation and apoptosis of skin cancer cells and induction of autophagy induced by ibrutinib were evaluated.. CCK8 plate cloning assays showed that ibrutinib can gradually inhibit the skin cancer cell proliferation as the treatment time and dose increased. Results of flow cytometry showed that apoptosis in skin cancer cells were induced after ibrutinib treatment. Western blot showed that autophagy in skin cancer cells was found induced by ibrutinib and also related to the time and concentration of ibrutinib treatment. Combination treatment of ibrutinib and 3MA for skin cancer cells can significantly increase apoptosis.. Ibrutinib has anti-tumor activity in skin cancer and can induce autophagy. Binding to autophagy inhibitors can promote ibrutinib's anti-skin cancer activity. Our experimental results provided new ideas for developing skin cancer drugs.

Topics: Adenine; Apoptosis; Autophagy; Autophagy-Related Protein 7; Cell Line, Tumor; Cell Proliferation; Humans; Microtubule-Associated Proteins; Piperidines; Pyrazoles; Pyrimidines; Skin Neoplasms

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an

Topics: Adenine; Aged, 80 and over; Antineoplastic Agents; CARD Signaling Adaptor Proteins; Disease Progression; Female; Genomic Instability; Guanylate Cyclase; Humans; I-kappa B Proteins; Interferon Regulatory Factors; Lymphatic Metastasis; Lymphoma, Large B-Cell, Diffuse; Mutation; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Skin Neoplasms

Topics: Adenine; Aged; Aged, 80 and over; Humans; Male; Mohs Surgery; Piperidines; Postoperative Hemorrhage; Pyrazoles; Pyrimidines; Risk Factors; Skin Neoplasms

Topics: Adenine; Aged; Antineoplastic Agents; Fatal Outcome; Humans; Lymphoma, Mantle-Cell; Male; Piperidines; Pyrazoles; Pyrimidines; Retreatment; Skin Neoplasms