A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1)

Ramalingam, Suresh S.; Goss, Glenwood D.; Rosell, Rafael; Schmid-Bindert, Gerald; Zarić, Bojan; Andrić, Zoran; Bondarenko, Igor; Комов, Д. В.; Cerić, Timur; Khuri, Fadlo R.; Samaržija, Miroslav; Felip, Enriqueta; Ciuleanu, Tudor-Eliade; Hirsh, Vera; Wehler, Thomas; Spicer, James; Salgia, Ravi; Shapiro, Geoffrey I.; Sheldon, E.; Teofilovici, Florentina; Vukovic, Vojo; Fennell, Dean A.

doi:10.1093/annonc/mdv220

Cited by 89 publications

(57 citation statements)

References 14 publications

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“…Furthermore, the key role of CDC25C in mediating bypass of the G 2 /M checkpoint after Hsp90 inhibition provides a novel target to restore this checkpoint and develop for the clinic. Finally, these results could serve as an explanation for the failure of the GALAXY 2 trial (29,52,53). …”

Section: Discussionmentioning

confidence: 81%

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

Chatterjee

Huang

Christie

et al. 2017

Molecular Cancer Therapeutics

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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.

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Section: Discussionmentioning

confidence: 81%

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

Chatterjee

Huang

Christie

et al. 2017

Molecular Cancer Therapeutics

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“…The feasibility of the clinical use of HSP90 inhibitors has already been demonstrated in several clinical trials. 23,32 The potential synergism between inhibitors targeting HSP90 and specific BCR-dependent kinases should be explored in future studies. Because HSP90 inhibitors target several important BCR signaling effectors at once, they might also become a valuable tool in the context of kinase inhibitor resistance, which is driven by mutations in the target kinase itself or bypass mechanisms through other cell survival promoting kinases.…”

Section: Discussionmentioning

confidence: 99%

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

Walter

Pan

Doebele

et al. 2017

Blood

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Key Points• HSP90 inhibition induces apoptosis in BL cells by disrupting tonic BCR signaling.• SYK is an HSP90 client protein, and BCR signalingdependent phosphorylation of HSP90 on Y197 is required for this interaction.Burkitt lymphoma (BL) is an aggressive B-cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Because of their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling, we show that, in BL, HSP90 inhibition compromises the activity of the pivotal B-cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Together, our results demonstrate that HSP90 inhibition impairs BL cell survival by interfering with tonic BCR signaling, thus providing a molecular rationale for the use of HSP90 inhibitors in the treatment of BL. (Blood. 2017;129(5):598-608)

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“…Combination studies with chemotherapy are ongoing, although they do not specifically enrich for KRAS mutations [129]. In a phase II trial of ganetespib and docetaxel, the combination failed to improve PFS or OS in patients with KRAS-mutant lung cancer [130]. Another trial of retaspimycin in combination with docetaxel failed to improve overall survival compared with docetaxel/placebo (NCT01362400) [131].…”

Section: Targeting Hsp90mentioning

confidence: 99%

Targeting the KRAS Pathway in Non-Small Cell Lung Cancer

et al. 2016

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Lung cancer remains the leading cause of cancer‐related deaths worldwide. However, significant progress has been made individualizing therapy based on molecular aberrations (e.g., EGFR, ALK) and pathologic subtype. KRAS is one of the most frequently mutated genes in non‐small cell lung cancer (NSCLC), found in approximately 30% of lung adenocarcinomas, and is thus an appealing target for new therapies. Although no targeted therapy has yet been approved for the treatment of KRAS‐mutant NSCLC, there are multiple potential therapeutic approaches. These may include direct inhibition of KRAS protein, inhibition of KRAS regulators, alteration of KRAS membrane localization, and inhibition of effector molecules downstream of mutant KRAS. This article provides an overview of the KRAS pathway in lung cancer and related therapeutic strategies under investigation. Implications for Practice: The identification of oncogene‐addicted cancers and specific inhibitors has revolutionized non‐small cell lung cancer (NSCLC) treatment and outcomes. One of the most commonly mutated genes in adenocarcinoma is KRAS, found in approximately 30% of lung adenocarcinomas, and thus it is an appealing target for new therapies. This review provides an overview of the KRAS pathway and related targeted therapies under investigation in NSCLC. Some of these agents may play a key role in KRAS‐mutant NSCLC treatment in the future.

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A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1)

Cited by 89 publications

References 14 publications

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

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

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

Targeting the KRAS Pathway in Non-Small Cell Lung Cancer

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