Association between anaplastic lymphoma kinase rearrangements (rALK) and the clinical activity of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with non-small cell lung cancer (NSCLC).

Sequist, Lecia V.; Natale, Ronald B.; Senzer, Neil; Martins, R. G.; Lilenbaum, Rogério; Gray, Jhanelle E.; Borger, Darrell R.; Paez, G.; Grayzel, David; Gettinger, Scott

doi:10.1200/jco.2010.28.15_suppl.7517

Cited by 6 publications

(3 citation statements)

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“…The effects of TAE684 on growth were also mirrored at the level of ALK phosphorylation (Figure 4B). Recent clinical studies have identified anti-tumor activity of the HSP90 inhibitor IPI-504 in ALK translocated NSCLC (17). We thus evaluated the effects of the HSP90 inhibitor 17-AAG in models harbouring the F1174L mutation (Figure 4C).…”

Section: Resultsmentioning

confidence: 99%

The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated Cancers

et al. 2010

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The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers.

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Section: Resultsmentioning

confidence: 99%

The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated Cancers

et al. 2010

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“…Nonetheless, HSP90 inhibition tripled the survival of treated mice, indicating the importance of the initial tumor response. Of note, the geldnamycin IPI-504 has demonstrated preliminary activity in NSCLC in a phase III trial; 2 of 5 patients who achieved partial response had tumors harboring EML4-ALK translocations (49). These clinical findings further highlight the similarities of our mouse model to human EML4-ALK NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ALK, PI3K/MEK, and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene

et al. 2010

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Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRAS or EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement. Cancer Res; 70(23); 9827-36. Ó2010 AACR.

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“…The ORR was 67% in patients with ALK rearrangement compared to 8.3% in those without the ALK rearrangement [32]. In another Phase I/II trial of IPI-504 in patients with NSCLC who had progressed on prior EGFR tyrosine kinase inhibitors (TKIs), two out of three patients with ALK rearrangement had a PR and a third patient had SD > 7.2 months with 24% reduction in tumor size [29].…”

Section: First-generation Hsp90 Inhibitors In Clinic – Lessons Leamentioning

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

156

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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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Association between anaplastic lymphoma kinase rearrangements (rALK) and the clinical activity of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with non-small cell lung cancer (NSCLC).

Cited by 6 publications

References 0 publications

The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated Cancers

The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated Cancers

Inhibition of ALK, PI3K/MEK, and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene

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

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