Providing improved treatment options for NSCLC remains a daunting challenge for clinicians and oncologists worldwide. Systemic combination chemotherapy is considered the standard of care for patients with advanced NSCLC despite intense efforts at modifying treatments toward improving survival outcomes [3
]. The use of standard chemotherapy is restricted to a defined number of cycles, as continuation results in added toxicity without meaningful improvements in progression-free or overall survival [27
]. The addition of a third cytotoxic agent to the two-drug combination has been evaluated, however no differences in efficacy were seen and the toxicity profile worsens [28
]. More recently, the use of maintenance therapy has evolved as a promising treatment option for NSCLC, based on emerging clinical data using novel molecularly targeted agents or chemotherapeutic drugs that exhibit a more favorable therapeutic index [6
One strategy to improve objective response rates in patients is through the use of molecularly targeted agents in combination with front line chemotherapeutics, such as bevacizumab and cetuximab. Indeed, combining complimentary agents that possess different presumed mechanisms of action and non-overlapping toxicities has proven important for the control of many human malignancies [29
]. This biologically rational approach in NSCLC has revealed that benefit from targeted therapy combinations [5
] is typically observed within subsets of patients and correlates with specific tumor histology and/or molecular phenotypes [8
]. The coordinate impact of Hsp90 blockade on multiple oncogenic pathways and processes, as well as substantial evidence of the clinical promise of using Hsp90 inhibitors in combination with other therapeutic agents [30
], provide a compelling rationale for investigating novel combinatorial strategies. Ganetespib is a next generation Hsp90 inhibitor, structurally unrelated to the prototypic ansamycin class, which exhibits superior pharmacologic and biological properties in terms of potency and safety [17
]. Accordingly, an important finding of this study is that ganetespib greatly enhances the efficacy of chemotherapeutics commonly used in the treatment of advanced NSCLC.
Here we showed that ganetespib synergistically potentiated the cytotoxic and antitumor activity of paclitaxel or docetaxel in a panel of NSCLC cell lines both in vitro and in vivo. As a single agent, ganetespib treatment resulted in loss of EGFR client protein expression and blockade of AKT signaling in the H1975 cell line, and significantly suppressed H1975 tumor growth in vivo when used in combination with paclitaxel or docetaxel. These findings are in agreement with a previous report showing that degradation of mutant EGFR and inhibition of AKT activity by the ansamycin Hsp90 inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) could sensitize NSCLC tumors to paclitaxel [24
]. In addition, the Hsp90 inhibitor CUDC-305 was recently shown to potentiate paclitaxel activity in H1975 xenografts [31
] where it was proposed that this occurred, at least in part, via suppression of AKT. Other studies in breast and ovarian cancer cell lines have also suggested that suppression of AKT activity by 17-AAG resulted in an enhanced sensitivity to the proapoptotic effects of paclitaxel [23
]. In this regard, we have additionally found that ganetespib treatment promotes synergistic improvements in docetaxel activity in breast, colon and prostate cell lines (D. Proia, unpublished observations). Taken together, these data imply that the modulation of Hsp90 function and consequent loss of pro-survival pathways may render cancer cells more susceptible to taxane treatment, and that this mechanism is conserved across tumor types.
However, the mechanism(s) by which ganetespib achieves improved therapeutic indices in combination with taxanes is likely to be multifactorial. Other, not mutually exclusive, molecular interactions likely exist - including complementary effects of ganetespib on the cell cycle machinery that enhance taxane activity. Paclitaxel and docetaxel each cause microtubule stabilization, mitotic arrest of cycling tumor cells, and subsequent apoptosis. Ganetespib treatment itself exerts profound effects on cell cycle regulatory proteins, in addition to oncogenic signaling pathways, that contribute to its potent antitumor activity [26
]. Further, it is known that mitotic catastrophe can be exacerbated by Hsp90 inhibition in cell lines with defects in the function of the cell checkpoint regulators BRCA1 [33
] and RB [22
], an effect presumably linked to interference with Hsp90’s role in centrosome organization [34
]. The Hsp90 client protein CRAF has also now been shown to localize to the mitotic spindle of proliferating tumor cells to promote progression in a MEK-independent manner [36
]. Inhibition of this process results in prometaphase arrest thus providing another avenue for targeted mitotic interference by Hsp90 inhibitors. It is reasonable to suggest, therefore, that modulation of the cell division machinery may represent an important component of the cytotoxic sensitizing property of ganetespib. This premise is supported by our findings that additive and synergistic benefit was also seen for ganetespib in combination with vincristine, another microtubule-targeted agent that induces mitotic arrest prior to cell death.
Notably, we observed that concurrent exposure to ganetespib and docetaxel was significantly more efficacious than either agent alone in 5 of 6 xenograft models in mice bearing established NSCLC tumors. In the one exception, H2228 cells, it appeared that the concentrations tested masked any potential benefit as each drug alone caused pronounced antiproliferative effects. These data have important clinical considerations. Docetaxel is the only agent that is approved for both first- and second-line therapy in advanced NSCLC [4
]. Meta-analyses of the current treatment regimens for these patients have shown that docetaxel is associated with better disease control than paclitaxel combinations [3
]. In addition, tumor histology does not exert any influence over the activity or efficacy of docetaxel, as opposed other third-generation cytotoxics [3
]. Thus, docetaxel represents an optimal front line candidate for combination with a targeted agent such as ganetespib. In light of these observations, we have recently initiated a Phase 2b/3 trial evaluating this combination in patients with refractory NSCLC.
In summary, the capacity of ganetespib to potentiate the cytotoxic effects of taxanes, in particular docetaxel, provides a molecular rationale for combining these agents as a clinical strategy for NSCLC. Overall, the data presented here provide strong preclinical support for the exploration of this combination as a novel therapeutic approach in patients suffering from this disease.