The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer

Abstract

Small molecule inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase activity, such as erlotinib and gefitinib, revolutionized therapy for non-small cell lung cancer (NSCLC) patients whose tumors harbor activating EGFR mutations. However, mechanisms to overcome the invariable development of acquired resistance to such agents, as well as realizing their full clinical potential within the context of wild-type EGFR (WT-EGFR) disease, remain to be established. Here, the antitumor efficacy of targeted EGFR tyrosine kinase inhibitors (TKIs) and the HSP90 inhibitor ganetespib, alone and in combination, were evaluated in NSCLC. Ganetespib potentiated the efficacy of erlotinib in TKI-sensitive, mutant EGFR-driven NCI-HCC827 xenograft tumors, with combination treatment causing significant tumor regressions. In erlotinib-resistant NCI-H1975 xenografts, concurrent administration of ganetespib overcame erlotinib resistance to significantly improve tumor growth inhibition. Ganetespib co-treatment also significantly enhanced antitumor responses to afatinib in the same model. In WT-EGFR cell lines, ganetespib potently reduced cell viability. In NCI-H1666 cells, ganetespib-induced loss of client protein expression, perturbation of oncogenic signaling pathways, and induction of apoptosis translated to robust single-agent activity in vivo. Dual ganetespib/erlotinib therapy induced regressions in NCI-H322 xenograft tumors, indicating that the sensitizing properties of ganetespib for erlotinib were conserved within the WT-EGFR setting. Mechanistically, combined ganetespib/erlotinib exposure stabilized EGFR protein levels in an inactive state and completely abrogated extracellular-signal-regulated kinase (ERK) and AKT signaling activity. Thus, selective HSP90 blockade by ganetespib represents a potentially important complementary strategy to targeted TKI inhibition alone for inducing substantial antitumor responses and overcoming resistance, in both the mutant and WT-EGFR settings.Electronic supplementary materialThe online version of this article (doi:10.1007/s11523-014-0329-6) contains supplementary material, which is available to authorized users.

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

“…However, these kinases are clients of, and binding strongly to HSP90 [173]. It is therefore not surprising that HSP90 inhibitor Ganetespib, combined with inhibitor Gilotrif of such kinases would reduce the synthesis of other HSPs other than HSP90 (because HSP90 is bound to heat shock factor 1; see Figure 2), and would enhance the inhibition of the mTORC1 pathway, causing stronger anti-cancer effects (as compared to the situation using Gilotrif alone) in in vivo mice model study reported [174], in our opinion.…”

Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells

“…Compared to the routine combination therapy that blocks the bypassed signals concomitantly, inhibition of Hsp90 offers a more feasible and effective way to overcome resistance because the kinases accounting for gefitinib resistance retain a high affinity for Hsp90 binding [31] . Notably, multiple recent preclinical and clinical investigations have highlighted the potential of the application of Hsp90 inhibitors such as NVP-AUY922 and ganetaspib to suppress the proliferation of gefitinib-resistant cells [32][33][34][35][36] .…”

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

“…The strong HSP90/EGFR interaction has then been used to propose an alternative therapeutic strategy combining an HSP90 inhibitor with an EGFR inhibitor. Interestingly, this combination (with the EGFR inhibitor erlotinib) resulted in prolonged animal survival in nonmutated and erlotinib-resistant models [67,68,70,71,114,115].…”