Abstract 2942: p90 Ribosomal S6 kinase mediates acquired resistance to ganetespib in KRAS mutant NSCLC
Authors: Chatterjee Suman , Huang Eric H-B. , Burns Timothy F. 
Published: July 2016

Approximately 25% of non-small cell lung cancer (NSCLC) patients have KRAS mutations and no current therapies targeting this key oncogenic driver exist. There is a critical need for novel agents targeting KRAS mutant NSCLC. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone required for the stability of its ‘client’ oncoproteins, which include a number of KRAS downstream effectors. Therefore, targeting Hsp90 could be a promising therapeutic intervention against “undruggable” KRAS driven tumors. Although single agent activity has been demonstrated with the HSP90 inhibitor ganetespib in vitro, only transient responses have been observed in the clinic in KRAS mutant patients. Our goal is to characterize the mechanisms of acquired resistance to ganetespib and develop rational combinations to overcome ganetespib resistance.

We have generated ganetespib resistant (GR) KRAS mutant NSCLC cells and demonstrated that bypass of G2/M arrest and hyper-activation of RAF/MEK/ERK and PI3K/AKT/MTOR pathways contribute to resistance. We observed increased dependence on these pathways as the GR cells were more sensitive to ERK1/2 or dual PI3K/MTOR inhibition. Moreover, the combination of ganetespib with ERK1/2 or PI3K/MTOR inhibitors was more effective than either single agent alone. Furthermore, several key mediators of G2/M progression were significantly increased in the GR cells compared to sensitive parental cell lines. Most notably, the serine/threonine kinase p90 ribosomal S6 kinase (p90-RSK), an important regulator of G2/M progression and the PI3K/AKT/MTOR pathway and a key target of ERK1/2 and PDK1 phosphorylation, were significantly upregulated both in expression and activity. Downstream p90-RSK targets and critical G2/M regulators - cdc25A, cdc25B, and cdc25C were also significantly elevated in GR cells. The p90-RSK family consists of four closely related isoforms (1-4), that are widely expressed in cancer and demonstrated to increase cell survival and proliferation. We observed that isoform-specific genetic silencing and pharmacological inhibition of p90-RSK re-sensitized GR cells to ganetespib. Conversely, overexpression of distinct p90-RSK isoforms in sensitive parental cell lines induced ganetespib resistance as well as led to bypass of ganetespib-induced G2/M arrest. The combination of ganetespib with p90-RSK inhibitor(s) enhanced cytotoxicity compared with either agent alone. These data suggest that combination of ganetespib with ERK1/2 or dual PI3K/mTOR or p90-RSK inhibitors may prevent ganetespib resistance and/or overcome acquired resistance after single agent treatment. These findings provide preclinical rationale for a potential future clinical study with an HSP90 inhibitor and a dual PI3K/mTOR inhibitor or RSK inhibitor in KRAS mutant NSCLC patients.

Citation Format: Suman Chatterjee, Eric H-B. Huang, Timothy F. Burns. p90 Ribosomal S6 kinase mediates acquired resistance to ganetespib in KRAS mutant NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2942.