Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

Sang, Jim; Acquaviva, Jaime; Friedland, Julie C.; Smith, Donald L.; Sequeira, Manuel; Zhang, Chaohua; Jiang, Qin; Xue, Liquan; Lovly, Christine M.; Jimenez, John Paul; Shaw, Alice T.; Doebele, Robert C.; He, Suqin; Bates, Richard C.; Camidge, D. Ross; Morris, Stephan W.; El‐Hariry, Iman; Proia, David A.

doi:10.1158/2159-8290.cd-12-0440

Cited by 196 publications

(203 citation statements)

References 48 publications

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“…In contrast, we now report that very modest, sustained inhibition of HSP90, at well-tolerated levels that do not deplete clients on their own or activate HSF1, reduces heterogeneity in the response of tumors to antiestrogens and prolongs the duration of disease control by these agents. Focusing on these striking effects of low-level, noncytotoxic HSP90 inhibition, the current study provides a new perspective, one very different from the many previous reports describing interesting activity for high-level HSP90 inhibition against recurrent drug-resistant cancers (33)(34)(35)(36) or synergistic interaction with other chemotherapeutics to increase their activity (37)(38)(39). From a translational perspective, the recent development of orally bioavailable HSP90 inhibitors should make sustained, low-level inhibitor exposure feasible in patients.…”

mentioning

confidence: 92%

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Whitesell

Santagata

Mendillo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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111

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The efficacy of hormonal therapies for advanced estrogen receptorpositive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.estrogen receptor | antiestrogen | drug resistance | tumor progression | tamoxifen D rastically limiting the efficacy of targeted therapeutics, the emergence of drug resistance in advanced cancers remains nearly inevitable. From yeast to vertebrates, the molecular chaperone heat shock protein 90 (HSP90) allows organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs and environmental stressors (1, 2). It does so by regulating the folding of a highly diverse portfolio of metastable client proteins, many mediating adaptive responses (3, 4).However, this role for HSP90 in adaptation is greatly magnified by its ability to promote the evolution of heritable new traits. To buffer the proteome against unexpected environmental challenges, HSP90 is present in large excess under normal circumstances. This buffering capacity allows it to modulate the manifestation of preexisting and newly acquired genetic variation within heterogeneous populations of cells, and even whole organisms, thereby dramatically expanding the range of phenotypes on which selection can act (1, 2, 5-7). As a dramatic, therapeutically relevant example, we have shown that this HSP90 buffer enables fungal pathogens spanning ∼1 billion years of evolution to evolve and maintain resistance to every major a...

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confidence: 92%

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Whitesell

Santagata

Mendillo

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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111

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“…Hsp90 inhibitors induce the degradation of EML4-ALK variant 1 and regression in some EML4-ALK-positive tumor models (7,9,10). Furthermore, clinical efficacy of an Hsp90 inhibitor in EML4-ALK NSCLC has been confirmed (11), and clinical trials are ongoing.…”

mentioning

confidence: 98%

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

Richards

Law

Rennalls

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

142

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Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners. structural biology | stratified medicine

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“…These drugs are currently under evaluation in combination with ALK inhibitors, postulating the synergistic effect of direct kinase inhibition and disruption of cell signaling (123,124). Nevertheless, the outstanding activity of novel ALK inhibitors, as well as their sub-optimal toxicity profiles, does not allow to allocate HSP90 combinations among the plausible future breakthrough for the treatment of ALKpositive patients.…”

Section: Positioning In Clinical Practicementioning

confidence: 99%

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti¹,

Tiseo²,

Maïo³

et al. 2016

Transl. Lung Cancer Res.

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Abstract:Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/ RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

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Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non–Small Cell Lung Cancer

Cited by 196 publications

References 48 publications

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

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