RESUMO
In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+ samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients.
RESUMO
Several animal and human investigations have indicated that intraocular pressure (IOP) levels may be associated with extreme drug-induced changes in the extraocular muscles. Further, recent data suggest that, among individuals with normal IOP level, moderate increases in facial muscle (EMG) activity around the eye while the eye is open are associated with increases in IOP. To investigate further the relationship between facial EMG activity and IOP levels and to examine a group of individuals with elevated IOP levels, subjects were recruited from outpatients at an optometry clinic. Three groups of subjects were selected: a group of ocular hypertensive subjects who showed elevated pressures at the optometry clinic and upon the day of testing, a group of labile ocular hypertensive subjects who evinced elevated pressures during their visit to the optometry clinic but lower pressures on the day of testing, and a group of normal IOP subjects who showed normal pressures both during their optometry clinic visit and on the day of testing. To investigate anxiety differences, subjects were administered the State-Trait Anxiety Inventory, but subsequent analysis revealed no group differences. To evaluate the role of stress upon muscle (EMG) functioning around the eye, subjects were subjected to imagery and standardized mental arithmetic stressors; analyses of these results also revealed no significant group differences. Finally, subjects were given EMG biofeedback for muscle activity around the eye while IOP was assessed during five alternating periods in which they made decreases and increases in EMG activity. Results revealed significant group, period, and group by period interaction effects. The pattern of results is interpreted as implicating EMG activity in IOP fluctuations; the implications of these data for potential biofeedback and stress management treatments are discussed.