Targeting Hsp90 prevents escape of breast cancer cells from tyrosine kinase inhibition

Abstract

Recent studies have identified development of resistance to tyrosine kinase inhibition (TKI) as a significant roadblock to effective treatment. One mechanism of resistance recently appreciated involves 'oncogene switching', or the re-activation of signaling pathways by one or more redundant upstream activators. In breast cancer models, ErbB TKIs such as gefitinib have been shown to lose the ability to modulate ErbB-driven signaling pathways over time, even though ErbB inhibition is maintained. Although incomplete ErbB inhibition has been proposed to underlie this phenomenon, our findings suggest that oncogene switching can also re-activate downstream signaling pathways in breast cancer cells, even when ErbB inhibition is complete. We find that ErbB TKI-induced Src activation mediates downstream signaling rebound in SKBR3 cells, and we show that combination of Src and ErbB inhibitors is more effective and longlasting than is either TKI alone. Finally, the Hsp90 inhibitor 17-AAG, by simultaneously and durably inhibiting multiple signaling activators including ErbB and Src kinases, does not permit oncogene switching and results in a more prolonged and robust inhibition of downstream signaling pathways in breast cancer cells than do individual TKIs. These data support the continued clinical evaluation of Hsp90 inhibitors in breast cancer.

Cancer cells harboring MET gene amplification activate alternative signaling pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors

“…Similar observations regarding ErbB-driven cancers have recently been reported. 11 In the case of both ErbB-and c-Met-driven cancers, prolonged Hsp90 inhibition, in contrast to specific TKI, results in significant apoptosis, likely because the impact of Hsp90 inhibition is long-lasting and multifactorial. Importantly, although Hsp90 inhibitors are cleared rapidly from blood and normal tissues, pharmacologically active concentrations have been measured in tumor xenografts for at least 48 hours after a single bolus administration.…”

“…7,35 Other mechanisms allow cancer cells to utilize the inherent redundancy of cellular signaling networks to bypass the inhibited kinase while maintaining activation of downstream pathways. 9,11,35 Indeed, in NSCLC, MET amplification and c-Met activation have been suggested as one means of escape from, or inherent insensitivity to, EGFR TKI. 8,[36][37][38] Amplified c-Met has been reported to drive the activity of EGFR family members and, conversely, mutated and amplified EGFR can drive c-Met activity.…”

“…Continuous in vitro incubation with a specific TKI for several days is sufficient to supply the selective pressure necessary to trigger oncogene switching in some cell models. 10,11 Whether cells harboring MET gene amplification are capable of evading the effects of c-Met TKI Disparate response of signaling pathways downstream of c-Met to long-term exposure of H1993 cells to SU11274 or 17-AAG. Auto-phosphorylation of c-Met on tyrosine Y1349 in its C-terminal tail provides a docking site for recruitment of signal transducers.…”

Geldanamycin selectively targets the nascent form of ERBB3 for degradation

“…The binding of HSP90/CDC37 to the Src kinase Lck is stabilized by the Src family specific kinase inhibitor PP2 (Giannini and Bijlmakers 2004). For ERBB2, HSP90 binding to the mature receptor is sensitive to the irreversible and ERBB-specific kinase inhibitor CI-1033 (Citri et al 2002), and the inhibition of the ERBB2/HSP90 interaction by 17-AAG can suppress the escape from tyrosine kinase inhibition in ERBB2-overexpressing SKBR3 cells (Pashtan et al 2008). Interestingly, kinasedeficient mutants of both EGFR and ERBB2 display enhanced sensitivity to geldanamycin (Citri et al 2002), and this enhanced sensitivity to geldanamycin by kinasedeficient EGFR resides largely with the mature and cellsurface-localized species.…”

Heat Shock Proteins in Chronic Lymphocytic Leukaemia

“…In particular, HSPC1 appears to play a fundamental role in the development and maintenance of several tumour characteristics (Neckers, 2007). HSPC1 binds and stabilises a broad array of mutated oncoproteins Minami et al 2002;Pashtan et al 2008), so the targeting of this single chaperone, should in theory, destabilise and degrade a wide variety of signalling kinases, therefore simultaneously targeting a number of cell signalling pathways. Furthermore, by selectively inhibiting HSPC1, all six 'hallmarks of cancer' (Hanahan & Weinberg, 2001;Hanahan & Weinberg, 2011) can be targeted in parallel, thereby dramatically reducing the probability that a resistant clone will develop.…”