RESUMO
Cancer stem cell survival is the leading factor for tumor recurrence after tumor-suppressive treatments. Therefore, specific and efficient inhibitors of cancer stemness must be discovered for reducing tumor recurrence. YM155 has been indicated to significantly reduce stemness-derived tumorsphere formation. However, the pharmaceutical mechanism of YM155 against cancer stemness is unclear. This study investigated the potential mechanism of YM155 against cancer stemness in lung cancer. Tumorspheres derived from epidermal growth factor receptor (EGFR)-mutant HCC827 and EGFR wild-type A549 cells expressing higher cancer stemness markers (CD133, Oct4, and Nanog) were used as cancer stemness models. We observed that EGFR autophosphorylation (Y1068) was higher in HCC827- and A549-derived tumorspheres than in parental cells; this autophosphorylation induced tumorsphere formation by activating G9a-mediated stemness. Notably, YM155 inhibited tumorsphere formation by blocking the autophosphorylation of EGFR and the EGFR-G9a-mediated stemness pathway. The chemical and genetic inhibition of EGFR and G9a revealed the significant role of the EGFR-G9a pathway in maintaining the cancer stemness property. In conclusion, this study not only revealed that EGFR could trigger tumorsphere formation by elevating G9a-mediated stemness but also demonstrated that YM155 could inhibit this formation by simultaneously blocking EGFR autophosphorylation and G9a activity, thus acting as a potent agent against lung cancer stemness.
Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Imidazóis/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Naftoquinonas/farmacologia , Afatinib , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metilação/efeitos dos fármacos , Fator 3 de Transcrição de Octâmero/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Quinazolinas/farmacologia , RNA Mensageiro/metabolismoRESUMO
Mutations in JAK2, MPL and CALR genes have been identified in the majority of myeloproliferative neoplasm (MPN) patients, and patients negative for these three mutations are the so-called triple-negative (TN) MPN. In this study, we examined the mutational profiles of 16 triple-negative MPN patients including 7 essential thrombocythemia (ET), 1 primary myelofibrosis and 8 polycythemia vera (PV). Targeted next-generation sequencing was performed using the ACTOnco Comprehensive Cancer Panel (Ion AmpliSeq Comprehensive Cancer Panel, Life Technologies) to target all coding exons of 409 cancer-related genes. Overall, 30 nonsynonymous somatic mutations were detected in 12 (75%) patients with a range of 1-5 mutations per sample. Notably, one ET patient was found to have JAK2V617F and KITP551L mutations at very low allele frequency. One MPLP70L and 1 MPLM602T mutations were identified each in 1 ET and 1 PV, respectively. Other recurrent mutations were also identified including KMT2C, KMT2D, IRS2, SYNE1, PDE4DIP, SETD2, ATM, TNFAIP3 and CCND2. In addition, germline mutations were also found in some cancer-related genes. Copy number changes were rare in this cohort of TN MPNs. In conclusion, both somatic and germline mutations can be detected in TN MPN patients.
Assuntos
DNA de Neoplasias/genética , Mutação , Transtornos Mieloproliferativos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Calreticulina/genética , Análise Mutacional de DNA/métodos , DNA de Neoplasias/sangue , Feminino , Mutação em Linhagem Germinativa , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/sangue , Receptores de Trombopoetina/genética , Análise de Sequência de DNA/métodosRESUMO
Oxaliplatin is a third-generation platinum analog that is used mainly to treat advanced colorectal cancer. The reported incidence of hypersensitivity reactions to oxaliplatin, especially after multiple cycles of therapy, is less than 1%. We report a patient with metastatic colon cancer who developed a hypersensitivity reaction to oxaliplatin during the sixth cycle of combination chemotherapy with oxaliplatin, high-dose 5-fluorouracil and leucovorin. The same reaction occurred again after re-exposure to oxaliplatin 2 weeks later even with prophylactic administration of steroids and H1 antihistamines. After failing third-line treatment with oral tegafur-uracil, we desensitized the patient by using a fixed-rate 24-h continuous infusion of dilute oxaliplatin (0.15 mg/ml), in addition to steroids and H1 antihistamines. He had no hypersensitivity reaction during or after that infusion or when the same concentration was infused in the same way 2 weeks later. Because his condition subsequently deteriorated and the cancer progressed, no further oxaliplatin was given. Our experience does demonstrate, however, that a fixed-rate 24-h continuous infusion of oxaliplatin in a low concentration may prevent a hypersensitivity reaction in a previously sensitized patient.