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Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib.

ABSTRACT:

Background

Tyrosine kinase inhibitors, such as crizotinib and erlotinib, are widely used to treat non-small-cell lung cancer, but after initial response, relapse is common because of the emergence of resistance through multiple mechanisms. Here, we investigated whether a frontline combination with an HSP90 inhibitor could delay the emergence of resistance to these inhibitors in preclinical lung cancer models.

Methods

The HSP90 inhibitor, onalespib, was combined with either crizotinib or erlotinib in ALK- or EGFR-activated xenograft models respectively (H2228, HCC827).

Results

In both models, after initial response to the monotherapy kinase inhibitors, tumour relapse was observed. In contrast, tumour growth remained inhibited when treated with an onalespib/kinase inhibitor combination. Analysis of H2228 tumours, which had relapsed on crizotinib monotherapy, identified a number of clinically relevant crizotinib resistance mechanisms, suggesting that HSP90 inhibitor treatment was capable of suppressing multiple mechanisms of resistance. Resistant cell lines, derived from these tumours, retained sensitivity to onalespib (proliferation and signalling pathways were inhibited), indicating that, despite their resistance to crizotinib, they were still sensitive to HSP90 inhibition.

Conclusions

Together, these preclinical data suggest that frontline combination with an HSP90 inhibitor may be a method for delaying the emergence of resistance to targeted therapies.

SUBMITTER: Courtin A

PROVIDER: S-EPMC5117788 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib.

Courtin Aurelie A Smyth Tomoko T Hearn Keisha K Saini Harpreet K HK Thompson Neil T NT Lyons John F JF Wallis Nicola G NG

British journal of cancer 20160927 9

<h4>Background</h4>Tyrosine kinase inhibitors, such as crizotinib and erlotinib, are widely used to treat non-small-cell lung cancer, but after initial response, relapse is common because of the emergence of resistance through multiple mechanisms. Here, we investigated whether a frontline combination with an HSP90 inhibitor could delay the emergence of resistance to these inhibitors in preclinical lung cancer models.<h4>Methods</h4>The HSP90 inhibitor, onalespib, was combined with either crizoti ...[more]

PMID: 27673365

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Project description:BackgroundHeat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination.DesignThis phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D).ObjectivesThe primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS).MethodsPatients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile.ResultsThirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months.ConclusionCombination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC.Trial registrationOnalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Project description:RationalCisplatin based cancer therapy is an affordable and effective standard therapy for several solid cancers, including lung, ovarian and head and neck cancers. However, the clinical use of cisplatin is routinely limited by the development of drug resistance and subsequent therapeutic failure. Therefore, methods of circumventing cisplatin resistance have the potential to increase therapeutic efficiency and dramatically increase overall survival. Cisplatin resistance can be mediated by alterations to the DNA damage response, where multiple components of the repair machinery have been described to be client proteins of HSP90. In the present study, we have investigated whether therapy with the novel HSP90 inhibitor onalespib can potentiate the efficacy of cisplatin and potentially reverse cisplatin resistance in ovarian and head and neck cancer cells.MethodsCell viability, cancer cell proliferation and migration capacity were evaluated in vitro on models of ovarian and head and neck cancer cells. Western blotting was used to assess the downregulation of HSP90 client proteins and alterations in downstream signaling proteins after exposure to cisplatin and/or onalespib. Induction of apoptosis and DNA damage response were evaluated in both monotherapy and combination therapy groups.ResultsResults demonstrate that onalespib enhances the efficiency of cisplatin in a dose-dependent manner. Tumor cells treated with both drugs displayed lower viability and a decreased migration rate compared to vehicle-control cells and cells treated with individual compounds. An increase of DNA double strand breaks was observed in both cisplatin and onalespib treated cells. The damage was highest and most persistent in the combination group, delaying the DNA repair machinery. Further, the cisplatin and onalespib co-treated cells had greater apoptotic activity compared to controls.ConclusionThe results of this study demonstrate that the reduced therapeutic efficacy of cisplatin due to drug-resistance could be overcome by combination treatment with onalespib. We speculate that the increased apoptotic signaling, DNA damage as well as the downregulation of HSP90 client proteins are important mechanisms promoting increased sensitivity to cisplatin treatment.

Dataset Information

Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib.

Background

Methods

Results

Conclusions

Publications

Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib.

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