Hsp90 Inhibition Suppresses Mutant EGFR-T790M Signaling and Overcomes Kinase Inhibitor Resistance

Shimamura, Takeshi; Li, Danan; Ji, Hongbin; Haringsma, Henry J.; Liniker, Elizabeth; Borgman, Christa L.; Lowell, April M.; Minami, Yuko; McNamara, Kate; Perera, Samanthi A.; Zaghlul, Sara; Thomas, Roman K.; Greulich, Heidi; Kobayashi, Susumu; Chirieac, Lucian R.; Padera, Robert F.; Kubo, Shigeto; Takahashi, Masaya; Tenen, Daniel G.; Meyerson, Matthew; Wong, Kwok-Kin; Shapiro, Geoffrey I.

doi:10.1158/0008-5472.can-07-5428

Cited by 138 publications

(127 citation statements)

References 46 publications

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“…5B). This mutation, T790M, enhances EGFR catalytic activity and confers resistance to reversible tyrosine kinase inhibitors (39). Our PD study in H1975 tumor shows that CUDC-305 is able to induce simultaneous degradation of multiple HSP90 client proteins in vivo, including mutant EGFR and key regulators of the RAF/MEK/ERK and PI3K/AKT signaling cascades downstream of EGFR (Fig.…”

mentioning

confidence: 82%

CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

Bao

Lai

Qü

et al. 2009

Clinical Cancer Research

103

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Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types. Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models.Results: CUDC-305 shows high affinity for HSP90α/β (IC 50 , ∼100 nmol/L) and HSP90 complex derived from cancer cells (IC 50 , 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC 50 , 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross bloodbrain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dosedependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non-small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models. Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.

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mentioning

confidence: 82%

CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

Bao

Lai

Qü

et al. 2009

Clinical Cancer Research

103

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“…HSP90 inhibitors have demonstrated efficacy in EGFR-mutant cell lines and murine models harboring secondary mutations, including T790M. 139 Clinical studies using HSP90 inhibitors in patients with EGFR TKI resistance are ongoing, but responses have been reported. 140 Preclinical and early clinical findings suggest that HSP90 inhibitors may also have activity in ALK-positive patients.…”

Section: Gainor and Shawmentioning

confidence: 99%

Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

Gainor

Shaw

2013

JCO

305

279

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A B S T R A C TThe success of tyrosine kinase inhibitors (TKIs) in select patients with non-small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

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“…Tumours with these mutations are also sensitive to HSP90 inhibitors despite developing resistance to TKIs. Tumour cells without EGFR mutations are equally resistance to both TKIs and HSP90 inhibitors (Shimamura et al, 2008) emphasising the importance of patient selection when designing clinical trials. Once active, EGFR is phosphorylated to initiate a series of biochemical signalling events, which diverge to activate the phosphatidylinositol 3-kinase AKT (PI3K-AKT) pathway, the Ras-Raf-extracellular signal-regulated kinase (Ras-Raf-ERK) pathway and the stress-activated protein kinase pathway.…”

Section: Prosurvival Signalling Moleculesmentioning

confidence: 99%

Targeting HSP90 for cancer therapy

et al. 2009

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Heat-shock proteins (HSPs) are molecular chaperones that regulate protein folding to ensure correct conformation and translocation and to avoid protein aggregation. Heat-shock proteins are increased in many solid tumours and haematological malignancies. Many oncogenic proteins responsible for the transformation of cells to cancerous forms are client proteins of HSP90. Targeting HSP90 with chemical inhibitors would degrade these oncogenic proteins, and thus serve as useful anticancer agents. This review provides an overview of the HSP chaperone machinery and the structure and function of HSP90. We also highlight the key oncogenic proteins that are regulated by HSP90 and describe how inhibition of HSP90 could alter the activity of multiple signalling proteins, receptors and transcriptional factors implicated in carcinogenesis.

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Hsp90 Inhibition Suppresses Mutant EGFR-T790M Signaling and Overcomes Kinase Inhibitor Resistance

Cited by 138 publications

References 46 publications

CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

CUDC-305, a Novel Synthetic HSP90 Inhibitor with Unique Pharmacologic Properties for Cancer Therapy

Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

Targeting HSP90 for cancer therapy

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