Hsp90 Inhibitor Ganetespib Overcomes Resistance and Packs a Punch against ALK+ Tumors

A new drug has shown promising efficacy in non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) gene mutation. Ganetespib overcame acquired resistance to the drug crizotinib and showed strong antitumor activity in mice. Ganetespib works by inhibiting a “chaperone” protein called Hsp90 and thus targets multiple cancer signaling pathways for a more complete and lasting effect.

Crizotinib (Xalkori) is currently the only FDA-approved treatment that specifically targets ALK, the mutated protein in a subtype of NSCLC. Like many tyrosine kinase inhibitors, however, crizotinib can have reduced efficacy if tumors acquire secondary mutations that confer drug resistance. An alternative approach to targeting a specific protein is to disrupt several cancer signaling pathways at once by inhibiting a so-called molecular chaperone. Hsp90, the chaperone protein, makes sure other proteins fold and function correctly. Ganetespib, the new drug, inhibits Hsp90, thus destroying downstream proteins that are vital for tumor survival, like the mutated ALK.

In both cancer cell cultures and mice grafted with tumors, researchers found that ganetespib showed more robust anticancer activity than crizotinib. In particular, ganetespib treatment was well-tolerated by the mice and was associated with significantly greater tumor shrinkage. The effects of the treatment also appeared to persist for longer, with cancer signaling pathways in tumors deactivated for at least 72 hours after administration of ganetespib. Tumorous mice treated with ganetespib also had longer overall survival.

Crucially, ganetespib was able to overcome the acquired resistance to crizotinib that tumor cells often develop over the course of treatment. Tumor cells that were resistant to crizotinib retained their sensitivity to ganetespib and displayed the expected reduced protein expression. Induced secondary mutations in the ALK gene that normally confer resistance to crizotinib were also no match for ganetespib.

In a separate phase II clinical study of ganetespib for gastrointestinal tumors, investigators found that the subset of patients with ALK mutations experienced longer progression-free survival, with 88% achieving disease control. In one patient, noticeable tumor shrinkage was seen with ganetespib treatment, despite disease progression with 12 months of prior crizotinib therapy. Ganetespib appears to be more potent and long-lasting compared to crizotinib because of its multimodal activity, inhibiting Hsp90, which in turn disrupts a number of other proteins and signaling pathways.

These results, combined with the new study published in Cancer Discovery, are encouraging news for ALK-positive NSCLC patients, according to Synta Pharmaceuticals, the developer of ganetespib. “Ganetespib therapy represents a new option for treating ALK-dependent lung cancer in sequence with direct ALK inhibitors, and/or for treating patients who relapse following direct ALK inhibitor therapy,” said David Proia, an author on the study and director of cancer biology at Synta. The combination treatment Proia alludes to may be particularly effective: cancer cell cultures dosed with both ganetespib and crizotinib showed increased cell death, while mice receiving the combination treatment had tumor shrinkage of 93%. The dual ganetespib–crizotinib treatment in mice yielded greater antitumor activity than crizotinib alone and was also better tolerated.