AT13387, discovered with a fragment based discovery approach

AT13387, discovered with a fragment based discovery approach, has also been characterized in NCI H1975 NSCLC cells. In vitro, a 7 hour exposure resulted in depletion of mutant EGFR lasting in excess of 168 hours. Following single dose exposure to mice bearing NCI H1975 xenografts, there was rapid clearance from blood with prolonged intratumoral retention of drug to 240 hours, however, similar to ganetespib, depleted mutant EGFR expression with downstream signaling was restored by 72 hours. An administration schedule on days 1, 4, 8, 12 and 16 led to similar tumor growth inhibition as a once weekly schedule, neither producing clear regressions, raising the possibility that consecutive day dosing schedules may be optimal in this model as well as in trials in which NSCLC patients with tumors harboring EGFR mutation are evaluated. To this end, once weekly, twice weekly and consecutive day dosing administration schedules of AT13387 are all under evaluation in Phase 1 trials. NVP AUY922, an isoxazole resorcinol, has been studied in multiple preclinical models. A wide variety of NSCLC cell lines, including those harboring EGFR mutation, are highly sensitive to NVP AUY922, with low nanomolar IC50s in 72 hour MTS assays. In vivo, AUY922 is also preferentially retained in tumor over plasma. In ERBB2 dependent BT 474 breast cancer xenografts, ERBB2 depletion occurred by 6 hours after a single dose, with restoration of expression by 48 hours. More sustained regression was noted with three times per week compared to once weekly administration, at the expense of significantly greater toxicity, manifesting with animal weight loss. Because substantial tumor growth inhibition was still noted with once weekly dosing, NVP AUY922 has been evaluated clinically with this schedule. Interestingly, in a Phase 2 NSCLC trial, confirmed partial responses were noted in patients with ALK positive tumors, but also among 5 of 35 patients with tumors harboring EGFR mutation. The kinetics of EGFR depletion in response to NVP AUY922 in preclinical EGFR dependent NSCLC models will therefore be of substantial interest in order to explain the preliminary efficacy of once weekly dosing in this subset. The efficient and prolonged depletion of ERBB2 in xenografts following HSP90 inhibitor exposure, and the substantial superiority of ganetespib over 17 AAG against BaF3 cells transformed to IL 3 independence by ERBB2 carrying an exon 20 YVMA activating insertion mutation, prompted us to evaluate ganetespib in a mouse model of lung adenocarcinoma driven by the same mutation. Previously, we showed that these tumors demonstrate only partial sensitivity to a dual EGFR ERBB2 tyrosine kinase inhibitor that is augmented by mTOR inhibition, which further extinguishes the ERBB2 driven signaling pathway.