Biomarkers That Predict Sensitivity to Heat Shock Protein 90 Inhibitors

Jhaveri, Komal; Chandarlapaty, Sarat; Iyengar, Neil M.; Morris, Patrick G.; Corben, Adriana D.; Patil, Sujata; Akram, Muzaffar; Towers, Russell; Sakr, Rita A.; King, Tari A.; Norton, Larry; Rosen, Neal; Hudis, Clifford A.; Modi, Shanu

doi:10.1016/j.clbc.2015.11.004

Cited by 11 publications

(16 citation statements)

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“…Since over- or under-expression of Hsp90 is seen in a variety of tumour types, sometimes in association with gene amplification or loss, and has prognostic impact [ 4 – 6 , 22 , 23 ], Hsp90 levels could themselves be of predictive value for Hsp90 inhibitor therapy. However, recent data from phase I/II trials of various solid tumour types found that Hsp90 levels are not a predictive biomarker for Hsp90 inhibitor response [ 24 ]. In this respect, the activity of Hsp90 in cancer cells is highly dependent on other chaperones and co-chaperones like AHA1, p23, HOP (also known as STIP1), CHIP (STUB1), Cdc37, Hsp40 and Hsp70 [ 25 , 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…To date, it is clear that some patients benefit, whilst others do not, a problem exemplified by our demonstration of plateau effects in some cell lines–patients with these types of tumours are unlikely to show any benefit. Thus, there is a need for predictive biomarkers, but the only strong indicator of response in a series of Phase I/II trials appears to be ErbB2 [ 24 ], whereas other markers including Hsp90, Hsp70, EGFR and steroid receptors were not predictive. This contrasts with the observations that triple-negative breast cancers (that lack ErbB2) may show a good response to Hsp90 inhibitors [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

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Intrinsic proteotoxic stress levels vary and act as a predictive marker for sensitivity of cancer cells to Hsp90 inhibition

et al. 2018

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Response of tumours to Hsp90 inhibitors is highly variable and their clinical effects are unpredictable, emphasising the need for a predictive marker. We postulated that sensitivity to Hsp90 inhibitors is connected to basal proteotoxic stress that makes cells dependent on Hsp90. Therefore, we assessed HSF1 as a general sensor of proteotoxic stress and correlated its activity with sensitivity to three separate small molecule Hsp90 inhibitors in seven breast cancer cell lines representing each of the different cancer subtypes. Flow cytometry was used to analyse the viability of breast cancer cell lines after Hsp90 inhibition. HSF1 activity was characterised by Ser326 phosphorylation and the transactivation capacity of HSF1 was determined by qPCR analysis of the ratios of HSF1-dependent (HOP, Hsp70) and HSF1-independent (CHIP) chaperones and cochaperone mRNAs. We show that the sensitivity of breast cancer cell lines to Hsp90 inhibition is highly variable. The basal levels of phosphorylated HSF1 also vary between cell lines and the magnitude of change in HSF1 phosphorylation after Hsp90 inhibition showed a negative correlation with sensitivity to Hsp90 inhibitors. Similarly, the basal transactivation capacity of HSF1, determined by the ratio of Hsp70 or HOP mRNA to CHIP mRNA level, is directly proportional to sensitivity to Hsp90 inhibitors. Increasing basal HSF1 activity by prior heat shock sensitised cells to Hsp90 inhibition. These results demonstrate that endogenous HSF1 activity varies between individual cancer cell lines and inversely reflects their sensitivity to Hsp90 inhibitors, suggesting that basal proteotoxic stress is an important and generalised predictor of response. Mechanistically, the data indicate that high endogenous proteotoxic stress levels sensitise to Hsp90 inhibition due to the inability to respond adequately to further proteotoxic stress. HSF1 activity therefore represents a potential biomarker for therapy with Hsp90 inhibitors, which may be useful for the rational design of future clinical studies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intrinsic proteotoxic stress levels vary and act as a predictive marker for sensitivity of cancer cells to Hsp90 inhibition

et al. 2018

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“…Our group conducted a retrospective study to explore potential biomarkers in patients treated with HSP90 inhibitors. Among many potential candidates analyzed (HER2, HSP90, HSP70, phosphotension homolog), HER2 was found to be the most important individual biomarker and the only one with correlation to response with HSP90 inhibitor therapy [ 44 ]. While tumor biopsies have been undertaken in some trials and can serve as a useful tool to establish target modulation, they provide only static information for a small part of the tumor and cannot account for the heterogeneity of metastatic tumor burden.…”

Section: Discussionmentioning

confidence: 99%

A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer

et al. 2017

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BackgroundTargeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer.MethodsIn this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy.ResultsDose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2–4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8–55).ConclusionThe RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer.Trial registrationClinicalTrials.gov NCT02060253. Registered 30 January 2014.

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“…To date, the only reliable way to predict response to HSP90 inhibition has been to identify those patients whose cancer is driven by a particular oncogene that is a very sensitive HSP90 client (e.g., HER2 in breast cancer or chimeric ALK in NSCLC) [97]. Nonetheless, clinical success in other tumor types that harbor HSP90 onco-clients has been limited so far and the failure of HSP90 inhibitors in these tumors remains poorly understood.…”

Section: Biomarkers and Diagnostics – Unmet Need In Hsp90 Therapymentioning

confidence: 99%

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

Jhaveri

Ochiana

Dunphy

et al. 2014

Expert Opinion on Investigational Drugs

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Introduction Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

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Biomarkers That Predict Sensitivity to Heat Shock Protein 90 Inhibitors

Cited by 11 publications

References 30 publications

Intrinsic proteotoxic stress levels vary and act as a predictive marker for sensitivity of cancer cells to Hsp90 inhibition

Intrinsic proteotoxic stress levels vary and act as a predictive marker for sensitivity of cancer cells to Hsp90 inhibition

A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

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