ErbB3 Expression Predicts Tumor Cell Radiosensitization Induced by Hsp90 Inhibition

Abstract

The ability to identify tumors that are susceptible to a given molecularly targeted radiosensitizer would be of clinical benefit. Towards this end, we have investigated the effects of a representative Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG), on the radiosensitivity of a panel of human tumor cell lines. 17DMAG was previously shown to enhance the radiosensitivity of a number of human cell lines, which correlated with the loss of ErbB2. We now report on cell lines in which 17DMAG induced the degradation of ErbB2, yet had no effect on radiosensitivity. In a comparison of ErbB family members, ErbB3 protein was only detectable in cells resistant to 17DMAG-induced radiosensitization. To determine whether ErbB3 plays a casual role in this resistance, short interfering RNA (siRNA) was used to knockdown ErbB3 in the resistant cell line AsPC1. Whereas individual treatments with siRNA to ErbB3 or 17DMAG had no effect on radiosensitivity, the combination, which reduced both ErbB2 and ErbB3, resulted in a significant enhancement in AsPC1 radiosensitivity. In contrast to siRNA to ErbB3 or 17DMAG treatments only, AsPC1 cell exposure to the combination also resulted in a decrease in ErbB1 kinase activity. These results indicate that ErbB3 expression predicts for tumor cell susceptibility to and suggests that the loss of ErbB1 signaling activity is necessary for 17DMAG-induced radiosensitization. However, for cell lines sensitized by 17DMAG, treatment with siRNA to ErbB2, which reduced ErbB1 activity, had no effect on radiosensitivity. These results suggest that, whereas the loss of ErbB1 signaling may be necessary for 17DMAG-induced radiosensitization, it is not sufficient. (Cancer Res 2005; 65(15): 6967-75)

Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction

“…These results strongly suggest the role of Hsp90 and its clients in the restitution of IR-induced DNA fragmentation. This conclusion is consistent with recent findings that combined 17-DMAG/IR treatment inhibits DNA repair in two human pancreatic cell lines, analysed by a neutral Comet assay (Dote et al, 2005). Similarly, an alkaline Comet assay has also revealed an impaired radiation-induced DNA repair in DMAG-treated lung carcinoma H460 cells (Koll et al, 2008).…”

“…One of the proposed mechanisms to explain the radiosensitising effects of geldanamycins involves the selective degradation of several key proteins responsible for radioresistance, including ErbB2, EGFR, Raf-1 and Akt (for review, see Chinnaiyan et al, 2006). However, the degradation of ErbB2 induced either by 17-DMAG (Bull et al, 2004;Dote et al, 2005) or by siRNA (Dote et al, 2005) does not enhance the radiosensitivity of various carcinoma cell lines. These findings suggest the involvement of other mechanisms in the radiosensitising activity of Hsp90 inhibitors.…”

The ERBB3 receptor in cancer and cancer gene therapy

“…This apparent effect of high ERBB3 expression was demonstrated in pancreatic, prostate and mammary cancer cell lines. 340,430 Thus, ERBB3 is an attractive therapeutic target in its own right and indeed may be an essential one as part of any treatment protocol focused on control of ERBB receptors or the PI3K/AKT pathway. ERBB3 is not an easily druggable target due to lack of kinase activity.…”

“…Similarly specific downregulation of ERBB2 by an HSP90 inhibitor resulted in radiosensitization only in pancreatic cell lines that did not express ERBB3, and downregulation of ERBB3 by siRNA in other pancreatic cell lines resulted in acquisition of radiosensitivity, related to reduced tyrosine phosphorylation of EGFR. 340 Gastric cancers-ERBB3 showed increased expression in gastric cancers. 277,341,342 Both membrane and cytoplasmic staining were noted, whereas elevated ERBB3 in surrounding tissue was mainly cytoplasmic.…”

Análise da expressão e mecanismos de ação das proteínas Akt, Hsp90, mTOR e ciclina D1 em cultura de células de carcinoma epidermoide humano e células displásicas após irradiação com laser em baixa intensidade

“…Outra droga que está sendo investigada é a perifosina, um fosfolipídeo que inibe a ativação do Akt (53,54) e que se mostrou eficaz quando tratando linhagens celulares derivadas de carcinomas epidermoides de cabeça e pescoço (55) (68)(69)(70) , câncer de pulmão (71) , câncer colorretal (71)(72)(73) , câncer cervical (74,75) , câncer de bexiga (72) , câncer de pâncreas (69) , glioma (68,75) e melanoma (72) .…”