Reactivation of the p90RSK–CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2–M Arrest and Mediates Acquired Resistance to Ganetespib inKRAS-Mutant NSCLC

Abstract

A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations including the most frequently observed driver mutant KRAS which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Heat shock protein 90 (Hsp90) inhibitors appeared to be a promising therapy for KRAS mutant NSCLC, however limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G2/M cell cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C was critical for GR and mediated the bypass of a G2/M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G2/M arrest and induced ganetespib resistance in vitro and in vivo. Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i.

Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach

“…Recent preclinical research in our laboratory has led to the discovery of the ganetespib resistance mechanism in KRAS mutant NSCLCs. We have not only demonstrated that the acquired resistance to ganetespib in KRAS mutant NSCLC is due to the hyperactivation of critical ERK1/2-p90RSK-mTOR signaling arc and subsequent bypass of G 2 -M checkpoint arrest [ 274 , 275 ]. Moreover, we observed that ganetespib resistance led to cross resistance to the anti-microtubule agent, docetaxel, which could explain the failure of the Galaxy-2 trial [ 274 ].…”

“…We have not only demonstrated that the acquired resistance to ganetespib in KRAS mutant NSCLC is due to the hyperactivation of critical ERK1/2-p90RSK-mTOR signaling arc and subsequent bypass of G 2 -M checkpoint arrest [ 274 , 275 ]. Moreover, we observed that ganetespib resistance led to cross resistance to the anti-microtubule agent, docetaxel, which could explain the failure of the Galaxy-2 trial [ 274 ]. Although the failure of the Galaxy-2 trial led to cessation of any preclinical or clinical development of ganetespib, our preclinical analyses strongly suggest that the combination of ganetespib with an ERK1/2 inhibitor, or a p90RSK inhibitor or a CDC25C inhibitor would be an efficacious therapeutic strategy to test in the clinic [ 274 ].…”

“…Moreover, we observed that ganetespib resistance led to cross resistance to the anti-microtubule agent, docetaxel, which could explain the failure of the Galaxy-2 trial [ 274 ]. Although the failure of the Galaxy-2 trial led to cessation of any preclinical or clinical development of ganetespib, our preclinical analyses strongly suggest that the combination of ganetespib with an ERK1/2 inhibitor, or a p90RSK inhibitor or a CDC25C inhibitor would be an efficacious therapeutic strategy to test in the clinic [ 274 ]. Based on our results, we suggested that one of these inhibitors tested in this study with ganetespib or another HSP90 inhibitor that is currently under clinical evaluation (e.g., AT13387, NCT01712217 and TAS-116, NCT02965885) may well prevent acquired resistance to HSP90 inhibitor and/or help overcome the resistance after HSP90 inhibitor monotherapy [ 274 ].…”

Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients

“…HSP90, an upstream factor known to induce ERK/MAPK activation, and RPS6KA1, a downstream target of the ERK/MAPK signaling cascade, have been identified as therapeutically targetable. 35,36 There is also a reduction in the expression levels of well-established oncogenes, such as TGFBR3, FGFR2, FGFR4, LGR4, LGR5, PDGFRA, PDK3, SOX2, TCF19, E2F8, and MYB, by doxycycline (Table S2, online only). When comparing the genes downregulated by doxycycline with (1) those downregulated by PD98059 (data not shown) and (2) the gene set representing the ERK/MAPK pathway, we identified considerable overlap (Table S6, online only).…”

Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs

“…S6C; refs. 42,43). A common feature of cellular transformation is loss of cilia (10); for compounds causing increased ciliation, we also investigated whether they possessed similar activities in transformed cancer cells, as well as immortalized but nontransformed models.…”