RESUMEN
One-third of newly diagnosed adult acute myeloid leukaemia (AML) carry FLT3 mutations, which frequently occur together with nucleophosmin (NPM1) mutations and are associated with worse prognosis. FLT3 inhibitors are widely used in clinics with limitations due to drug resistance. AML cells carrying FLT3 mutations in both mouse models and patients present low expression of GATA1, a gene involved in haematopoietic changes preceding AML. Here, we show that FLT3 inhibition induces cellular responses and restores the GATA1 pathway and functions in NPM1/FLT3-ITD mutated AML, thus providing a new mechanism of action for this drug.
RESUMEN
BACKGROUND: In an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. PATIENTS AND METHODS: Tumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed. RESULTS: We observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab. CONCLUSIONS: In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptores ErbB/metabolismo , Genes erbB-2 , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Metástasis de la Neoplasia , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Trastuzumab , Resultado del TratamientoRESUMEN
BACKGROUND: Insulin-like growth factor receptor-1 (IGFR-1) represents a novel molecular target in non-small-cell lung cancer (NSCLC). IGFR-1 and epidermal growth factor receptor (EGFR) activation is essential to mediate tumor cell survival, proliferation and invasion. We explored the correlation between IGFR-1 and EGFR, their relationship with clinicopathological parameters and their impact on outcome in resected stage I-III NSCLC patients. PATIENTS AND METHODS: Tumors from 125 surgical NSCLC patients were evaluated for IGFR-1 and EGFR expression by immunohistochemistry. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS: IGFR-1 protein overexpression was detected in 36.0% of NSCLC patients and was associated with larger tumor size (P = 0.04) but not with other clinical or biological characteristics. EGFR protein overexpression was observed in 55.2% of NSCLC, more frequently in squamous cell carcinoma (SCC) than non-SCC (63.7% versus 36.3%, chi(2) = 9.8, P = 0.001). IGFR-1 protein expression was associated with EGFR protein expression (P = 0.03). At the multivariate analysis, high coexpression of both IGFR-1 and EGFR was a significant prognostic factor of worse disease-free survival (DFS) (hazard ratio 2.51, P = 0.01). CONCLUSION: A statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.