Abstract 4152: The p90RSK-CDC25C signaling pathway leads to bypass of the ganetespib induced G2/M arrest and mediates acquired resistance to ganetespib in KRAS mutant NSCLC

Abstract

Lung cancer is the leading cause of cancer death in the United States and worldwide. A large fraction of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations of which the most commonly observed driver is mutant KRAS. Unfortunately, NSCLC patients with oncogenic KRAS mutations have no effective therapies and prognosis is poor. As direct RAS targeting has been unsuccessful in the clinic to date, use of Heat shock protein 90 (Hsp90) inhibitors in KRAS mutant NSCLC appeared to be promising approach for targeting KRAS mutant NSCLC through its downstream effectors. However, limited clinical efficacy as monotherapy was observed due to rapid resistance. Furthermore, the combination of ganetespib and docetaxel was recently tested in a large phase III clinical trial (Galaxy-2) in advanced lung cancer and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to the Hsp90 inhibitor (Hsp90i), ganetespib by generating NSCLC cells with acquired resistance to Hsp90i’s including ganetespib (GR cells). We have not only identified the mechanism of acquired resistance to ganetespib but have also found that this mechanism induces cross resistance to docetaxel. Finally, we have identified novel Hsp90i combinations that can overcome and prevent this resistance. We report that hyperactivation of ERK and p90RSK and its downstream target, CDC25C leads to acquired resistance to ganetespib and docetaxel. Moreover, this resistance is mediated via bypass of a G2/M arrest. Overexpression of either p90RSK or CDC25C in naïve cells was sufficient to induce the bypass of this G2/M arrest as well induced resistance to both ganetespib and docetaxel. Remarkably, p90RSK or CDC25C overexpression also led to ganetespib resistance in vivo. The observed resistance was dependent on continued p90RSK/CDC25C signaling, as synthetic lethality to specific ERK, p90RSK or CDC25C inhibitors was observed. Importantly, we have found that the combination of ganetespib with inhibitors of ERK1/2, p90RSK, or CDC25C was highly efficacious. In summary, we propose that the hyperactivation of p90RSK induces CDC25C overexpression and activity which then induces G2/M progression via CyclinB1/cdc2 regulation resulting in ganetespib resistance. Despite two decades of testing in the clinic, either as monotherapy or in combination with chemotherapy, Hsp90 inhibitors have been ineffective due to acquired resistance. Our preclinical analyses provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90 inhibitors. Citation Format: Suman Chatterjee, Eric H. Huang, Ian Christie, Timothy F. Burns. The p90RSK-CDC25C signaling pathway leads to bypass of the ganetespib induced G2/M arrest and mediates acquired resistance to ganetespib in KRAS mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4152. doi:10.1158/1538-7445.AM2017-4152

Combination Treatment With Inhibitors of ERK and Autophagy Enhances Antitumor Activity of Betulinic Acid in Non–small-Cell Lung Cancer In Vivo and In Vitro

“…The extracellular signal-regulated kinases (ERKs) is frequently hyperactivated in many types of cancer, which is usually induced by activating mutations of the K-Ras that accounts for approximately 25% of NSCLC patients (Chatterjee et al, 2017). ERK can activate a series of transcription factors that orchestrate a complex cellular response, which is often considered as pro-proliferative (Brandt et al, 2019).…”