Browsing by Subject "KRAS"

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    EGFR, KRAS, BRAF, and PIK3CA characterization in squamous cell anal cancer
    (F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Martin, Vittoria; Zanellato, Elena; Franzetti-Pellanda, Alessandra; Molinari, Francesca; Movilia, Alessandra; Paganotti, Alessia; Deantonio, Letizia; De Dosso, Sara; Assi, Agnese; Crippa, Stefano; Boldorini, Renzo; Mazzucchelli, Luca; Saletti, Piercarlo; Frattini, Milo
    Background: Combined chemoradiation therapy is the gold standard in the treatment of squamous cell anal cancer (SCAC). However, even if the response rate is very high, many patients eventually relapse or experience a recurrence, thus requiring an invasive surgical procedure that has severe side effects. Most SCAC tumors overexpress epidermal growth factor receptor (EGFR); therefore, it is reasonable to consider anti-EGFR drugs as a new treatment option, as demonstrated by anecdotal reports. Promising results obtained in other solid tumors, both squamous and non-squamous, have revealed that an increase in the EGFR gene copy number may predict the efficacy of anti-EGFR therapies, while the presence of mutations in downstream members of the EGFR pathway may confer resistance. These markers have been only sporadically considered in SCAC. Methods: We investigated the status of the EGFR gene using FISH and examined KRAS, BRAF, and PIK3CA hot-spots mutations using sequencing analysis in a cohort of 84 patients affected by SCAC. Results: Twenty-eight patients (34%) showed an increase in EGFR gene copy number due to amplification (4%) or to polysomy (30%). KRAS and PIK3CA gene mutations were found in 4 (5%) and 13 patients (16%), respectively. No mutations were found in the BRAF gene. Conclusions: The characterization of the EGFR pathway may help in identifying different subgroups of SCAC that have specific molecular features, which may have implications in what targeted therapies are used to treat each patient. Histol Histopathol 29, 513-521 (2014)
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    NLRP3 inflammasome activation and symptom burden in KRAS-mutated CMML patients is reverted by IL-1 blocking therapy
    (Cell Press, 2023-12-19) Hurtado-Navarro, Laura; Cuenca-Zamora, Ernesto J; Zamora, Lurdes; Bellosillo, Beatriz; Such, Esperanza; Soler-Espejo, Eva; Martínez-Banaclocha, Helios; Hernández-Rivas, Jesus M.; Marco-Ayala, Javier; Martínez-Alarcón, Laura; Linares-Latorre, Lola; García-Ávila, Sara; Amat-Martínez, Paula; González, Teresa; Arnan, Monserrat; Pomares-Marín, Helena; Carreño-Tarragona, Gonzalo; Chen-Liang, Tzu Hua; Herranz, Maria T.; García-Palenciano, Carlos; Morales, María Luz; Jerez, Andrés; Lozano, Maria L.; Teruel-Montoya, Raul; Ferrer-Marín, Francisca; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
    Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cells proliferation and survival, and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibit NLRP3 inflammasome activation, reduce monocyte count, and improve the patient’s clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.