The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

Abstract

A ubiquitously expressed chaperone, heat shock protein 90 (HSP90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity. AT13387 (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, L-lactic acid salt) a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to HSP90 inhibition. The long duration of client protein knockdown and suppression of phospho-signaling seen in vitro after treatment with AT13387 was also apparent in vivo, with client proteins and phospho-signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of AT13387. Pharmacokinetic analyses indicated that while AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. AT13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer-acting HSP90 inhibitors, such as AT13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues. (Cancer Sci 2012; 103: 522-527) T he super-chaperone system is involved in the folding and maturation of newly synthesized proteins.(1,2) HSP90 in particular aids in the folding and maturation of a distinct subset of proteins, which includes kinases, cell surface receptors and transcription factors. (3,4) The N-terminal domain ATPase activity of HSP90 is essential for this function.(5) Inhibition of this domain induces remodeling of the HSP90 chaperone complex, resulting in the recruitment of ubiquitin ligases, polyubiquitination and subsequent proteasomal degradation of HSP90 client proteins.(6,7) Through this mechanism, the inhibition of a single target enzyme can have a wide effect on the stability and, hence, the function of a large set of client proteins. As many oncogenic proteins are HSP90 clients, HSP90 inhibition has been found to have broad antitumor effects.(8-10) In contrast to more recent targeted therapies, where the appearance of new driver mutations or resistance mutations result in a loss of efficacy, client protein mutation increases dependence on HSP90 chaperoning activity as these mutations tend to render the proteins less stable. (11)(12)(13) Previous studies have also demonstrated that the constitutively activated mutant forms of EGFR are particularly dependent on HSP90 both in vitro and in vivo, (14)(15)(16) indicating an HSP90 inhibitor may be particularly efficacious in mutant EGFR tumors.After HSP90 inhibiti...

First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors

“…First-generation geldanamycins and second-generation non-geldanamycin agents, including AT13387, as well as AUY922 and ganetespib, demonstrate preferential accumulation in tumors, with long intratumoral t 1/2 (often detectable for 7-10 days in tumor), justifying once-weekly regimens (11)(12)(13)(14). Here, AT13387 has demonstrated preliminary activity against KIT-driven GIST, including a partial response in a patient with tumor harboring mutations conferring resistance to TKIs.…”

“…Despite the long intratumoral t 1/2 noted with these agents, the suppression of client protein expression has been noted to be more transient. For example, in mutant EGFR (L858R/T790M) NCI-H1975 NSCLC xenografts, depletion of mutant EGFR has been documented to last a duration of 72 hours or shorter in response to a single dose of AT13387 or ganetespib (13,14). In a clinical evaluation of once-weekly ganetespib in GIST (29), tumor biopsies demonstrated only transient depletion of KIT and inhibition of downstream signaling pathways, suggesting that the once-weekly regimen was suboptimal for producing prolonged client protein depletion.…”

“…Exposure increased proportionally with increasing dose and demonstrated no accumulation or reduction on day 15 or day 18 versus day 1. Systemic pharmacokinetic exposures in the clinic at MTD dose(s) achieved levels associated with efficacy in preclinical xenograft studies when adjusted for differences in protein binding between nude mice and humans (11,14).…”

“…14, 15). In NSCLC NCI-H1975 xenografts harboring EGFR L858R/T790M, suppression of mutant EGFR expression occurred up to 72 hours after a single dose, with tumor growth inhibition achieved with twice-weekly dosing (14). Higher doses of AT13387, administered once weekly, also produced significant tumor growth inhibition (14).…”

Heat Shock Protein 90 Is a Potential Therapeutic Target in Cholangiocarcinoma

“…AT13387, a nonansamycin HSP90 inhibitor provided by Astex Pharmaceuticals, was reported to suppress cell growth of various cancer types (non-small-cell lung carcinoma, and nasopharyngeal carcinoma) by previous reports (28,29). No previous study reported, the effectiveness of AT13387 for cholangiocarcinoma cell lines; however, Shapiro and colleagues reported a phase I study of AT13387 for solid tumors, including one cholangiocarcinoma patient.…”