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Extended Survival and Prognostic Factors for Patients With ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastasis.
Johung KL, Yeh N, Desai NB, Williams TM, Lautenschlaeger T, Arvold ND, Ning MS, Attia A, Lovly CM, Goldberg S, Beal K, Yu JB, Kavanagh BD, Chiang VL, Camidge DR, Contessa JN
(2016) J Clin Oncol 34: 123-9
MeSH Terms: Adult, Aged, Anaplastic Lymphoma Kinase, Antineoplastic Agents, Brain Neoplasms, Carbazoles, Carcinoma, Non-Small-Cell Lung, Cranial Irradiation, Crizotinib, Disease-Free Survival, Female, Follow-Up Studies, Gene Rearrangement, Humans, Kaplan-Meier Estimate, Karnofsky Performance Status, Lung Neoplasms, Male, Middle Aged, Molecular Targeted Therapy, Neoplasm Staging, Piperidines, Prognosis, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Pyrazoles, Pyridines, Pyrimidines, Radiosurgery, Receptor Protein-Tyrosine Kinases, Risk Assessment, Risk Factors, Smoking, Sulfones
Show Abstract · Added January 26, 2016
PURPOSE - We performed a multi-institutional study to identify prognostic factors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and brain metastasis.
PATIENTS AND METHODS - A total of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutions; 84 of 90 patients received radiotherapy to the brain (stereotactic radiosurgery [SRS] or whole-brain radiotherapy [WBRT]), and 86 of 90 received tyrosine kinase inhibitor (TKI) therapy. Estimates for overall (OS) and intracranial progression-free survival were determined and clinical prognostic factors were identified by Cox proportional hazards modeling.
RESULTS - Median OS after development of brain metastases was 49.5 months (95% CI, 29.0 months to not reached), and median intracranial progression-free survival was 11.9 months (95% CI, 10.1 to 18.2 months). Forty-five percent of patients with follow-up had progressive brain metastases at death, and repeated interventions for brain metastases were common. Absence of extracranial metastases, Karnofsky performance score ≥ 90, and no history of TKIs before development of brain metastases were associated with improved survival (P = .003, < .001, and < .001, respectively), whereas a single brain metastasis or initial treatment with SRS versus WBRT were not (P = .633 and .666, respectively). Prognostic factors significant by multivariable analysis were used to describe four patient groups with 2-year OS estimates of 33%, 59%, 76%, and 100%, respectively (P < .001).
CONCLUSION - Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/or WBRT) and TKIs have prolonged survival, suggesting that interventions to control intracranial disease are critical. The refinement of prognosis for this molecular subtype of NSCLC identifies a population of patients likely to benefit from first-line SRS, close CNS observation, and treatment of emergent CNS disease.
© 2015 by American Society of Clinical Oncology.
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34 MeSH Terms
Anaplastic Lymphoma Kinase as a Therapeutic Target in Non-Small Cell Lung Cancer.
Iams WT, Lovly CM
(2015) Cancer J 21: 378-82
MeSH Terms: Anaplastic Lymphoma Kinase, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Clinical Trials as Topic, Drug Resistance, Neoplasm, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Recombination, Genetic, Translocation, Genetic, Treatment Outcome
Show Abstract · Added January 26, 2016
The therapeutic targeting of anaplastic lymphoma kinase (ALK) has been a burgeoning area of research since 2007 when ALK fusions were initially identified in patients with non-small cell lung cancer. The field has rapidly progressed through development of the first-generation ALK inhibitor, crizotinib, to an understanding of mechanisms of acquired resistance to crizotinib and is currently witnessing an explosion in the development of next-generation ALK inhibitors such as ceritinib, alectinib, PF-06463922, AP26113, X-396, and TSR-011. As with most targeted therapies, acquired resistance appears to be an inevitable outcome. Current preclinical and clinical studies are focused on the development of rational therapeutic strategies, including novel ALK inhibitors, as well as rational combination therapies to maximize disease control by delaying or overcoming acquired therapeutic resistance. This review summarizes the existing clinical data and ongoing research pertaining to the clinical application of ALK inhibitors in patients with non-small cell lung cancer.
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15 MeSH Terms
RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer.
Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM, Okimoto RA, Lin L, Neel DS, Sabnis A, Flanagan J, Chan E, Varella-Garcia M, Aisner DL, Vaishnavi A, Ou SH, Collisson EA, Ichihara E, Mack PC, Lovly CM, Karachaliou N, Rosell R, Riess JW, Doebele RC, Bivona TG
(2015) Nat Med 21: 1038-47
MeSH Terms: Anaplastic Lymphoma Kinase, Cell Line, Tumor, Drug Resistance, Neoplasm, Dual Specificity Phosphatase 6, Humans, Lung Neoplasms, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Oncogene Proteins, Fusion, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Receptor Protein-Tyrosine Kinases, ras Proteins
Show Abstract · Added January 26, 2016
One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.
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13 MeSH Terms
Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
Lovly CM, McDonald NT, Chen H, Ortiz-Cuaran S, Heukamp LC, Yan Y, Florin A, Ozretić L, Lim D, Wang L, Chen Z, Chen X, Lu P, Paik PK, Shen R, Jin H, Buettner R, Ansén S, Perner S, Brockmann M, Bos M, Wolf J, Gardizi M, Wright GM, Solomon B, Russell PA, Rogers TM, Suehara Y, Red-Brewer M, Tieu R, de Stanchina E, Wang Q, Zhao Z, Johnson DH, Horn L, Wong KK, Thomas RK, Ladanyi M, Pao W
(2014) Nat Med 20: 1027-34
MeSH Terms: Anaplastic Lymphoma Kinase, Crizotinib, Female, Gene Knockdown Techniques, Humans, Insulin Receptor Substrate Proteins, Lung Neoplasms, Middle Aged, Pyrazoles, Pyridines, Receptor Protein-Tyrosine Kinases, Receptor, IGF Type 1, Up-Regulation
Show Abstract · Added February 13, 2015
Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.
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13 MeSH Terms
Beyond histology: translating tumor genotypes into clinically effective targeted therapies.
Meador CB, Micheel CM, Levy MA, Lovly CM, Horn L, Warner JL, Johnson DB, Zhao Z, Anderson IA, Sosman JA, Vnencak-Jones CL, Dahlman KB, Pao W
(2014) Clin Cancer Res 20: 2264-75
MeSH Terms: Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Genetic Testing, Genetic Variation, Genomics, Genotype, Humans, Lung Neoplasms, Melanoma, Molecular Targeted Therapy, Mutation, Neoplasms, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Receptor Protein-Tyrosine Kinases
Show Abstract · Added March 10, 2014
Increased understanding of intertumoral heterogeneity at the genomic level has led to significant advancements in the treatment of solid tumors. Functional genomic alterations conferring sensitivity to targeted therapies can take many forms, and appropriate methods and tools are needed to detect these alterations. This review provides an update on genetic variability among solid tumors of similar histologic classification, using non-small cell lung cancer and melanoma as examples. We also discuss relevant technological platforms for discovery and diagnosis of clinically actionable variants and highlight the implications of specific genomic alterations for response to targeted therapy.
©2014 AACR.
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5 Members
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19 MeSH Terms
Analysis of major known driver mutations and prognosis in resected adenosquamous lung carcinomas.
Wang R, Pan Y, Li C, Zhang H, Garfield D, Li Y, Ye T, Hu H, Luo X, Li H, Zhang Y, Zhang J, Zhou X, Shen L, Pao W, Sun Y, Chen H
(2014) J Thorac Oncol 9: 760-8
MeSH Terms: Adenocarcinoma, Adult, Aged, Aged, 80 and over, Anaplastic Lymphoma Kinase, Carcinoma, Adenosquamous, Class I Phosphatidylinositol 3-Kinases, Disease-Free Survival, ErbB Receptors, Female, Genotype, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Oncogene Proteins, Fusion, Phosphatidylinositol 3-Kinases, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-ret, Proto-Oncogene Proteins p21(ras), Receptor Protein-Tyrosine Kinases, Receptor, ErbB-2, Survival Rate, ras Proteins
Show Abstract · Added March 10, 2014
INTRODUCTION - Genotyping for driver mutations is now routinely used to guide clinical care of patients with lung cancer. Adenosquamous lung carcinoma (AdSqLC) is a subtype of cancer that contains both adenocarcinoma and squamous cell carcinoma. However, the incidence, clinicopathologic characteristics, and prognostic implications of major driver mutations in AdSqLCs are not well established.
METHODS - Seventy-six resected AdSqLCs and 646 lung adenocarcinomas were screened for known genetic alterations involving EGFR, ERBB2, KRAS, BRAF, PIK3CA, AKT1, RET, and ALK. Tumors showing acinar, lepidic, micropapillary, or papillary growth in glandular component were classified as classical AdSqLC.
RESULTS - Of the 76 AdSqLCs, 43 (56.6%) harbored known mutant kinases, including 24 (31.6%) with EGFR mutations, eight (10.5%) with KRAS mutations, two (2.6%) with AKT1 (2.6%) mutations, one (1.3%) with ERBB2 insertion mutation, one (1.3%) with PIK3CA mutation, four (5.3%) with ALK fusions, and three (4%) with KIF5B-RET fusions. No mutation was found in BRAF. The mutational profiles and clinicopathologic characteristics of classical AdSqLC were strikingly similar to that of poorly differentiated adenocarcinoma. However, AdSqLCs with solid growth pattern in glandular component had high frequency of ALK or RET fusions and low EGFR mutation rate.
CONCLUSIONS - To our knowledge, this is the first comprehensive study investigating major oncogenic driver mutations in a large cohort of AdSqLC patients in a Chinese population. The findings suggest that it will be clinically valuable to investigate the growth pattern of glandular component in AdSqLCs.
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28 MeSH Terms
Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer.
Sang J, Acquaviva J, Friedland JC, Smith DL, Sequeira M, Zhang C, Jiang Q, Xue L, Lovly CM, Jimenez JP, Shaw AT, Doebele RC, He S, Bates RC, Camidge DR, Morris SW, El-Hariry I, Proia DA
(2013) Cancer Discov 3: 430-43
MeSH Terms: Adult, Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Crizotinib, Drug Resistance, Neoplasm, Female, HSP90 Heat-Shock Proteins, Humans, Lung Neoplasms, Male, Mice, Mice, Nude, Mice, SCID, Pyrazoles, Pyridines, Receptor Protein-Tyrosine Kinases, Triazoles, Tumor Burden, Xenograft Model Antitumor Assays, Young Adult
Show Abstract · Added September 3, 2013
UNLABELLED - EML4-ALK gene rearrangements define a unique subset of patients with non-small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a patient with crizotinib-resistant NSCLC. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC.
SIGNIFICANCE - In addition to direct kinase inhibition, pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK. The bioactivity profi le of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC.
©2013 AACR.
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2 Members
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23 MeSH Terms
Jelly Belly trans-synaptic signaling to anaplastic lymphoma kinase regulates neurotransmission strength and synapse architecture.
Rohrbough J, Kent KS, Broadie K, Weiss JB
(2013) Dev Neurobiol 73: 189-208
MeSH Terms: Anaplastic Lymphoma Kinase, Animals, Drosophila Proteins, Drosophila melanogaster, Electrophysiology, Immunohistochemistry, Receptor Protein-Tyrosine Kinases, Signal Transduction, Synapses, Synaptic Transmission
Show Abstract · Added March 29, 2017
In Drosophila, the secreted signaling molecule Jelly Belly (Jeb) activates anaplastic lymphoma kinase (Alk), a receptor tyrosine kinase, in multiple developmental and adult contexts. We have shown previously that Jeb and Alk are highly enriched at Drosophila synapses within the CNS neuropil and neuromuscular junction (NMJ) and postulated a conserved intercellular signaling function. At the embryonic and larval NMJ, Jeb is localized in the motor neuron presynaptic terminal whereas Alk is concentrated in the muscle postsynaptic domain surrounding boutons, consistent with anterograde trans-synaptic signaling. Here, we show that neurotransmission is regulated by Jeb secretion by functional inhibition of Jeb-Alk signaling. Jeb is a novel negative regulator of neuromuscular transmission. Reduction or inhibition of Alk function results in enhanced synaptic transmission. Activation of Alk conversely inhibits synaptic transmission. Restoration of wild-type postsynaptic Alk expression in Alk partial loss-of-function mutants rescues NMJ transmission phenotypes and confirms that postsynaptic Alk regulates NMJ transmission. The effects of impaired Alk signaling on neurotransmission are observed in the absence of associated changes in NMJ structure. Complete removal of Jeb in motor neurons, however, disrupts both presynaptic bouton architecture and postsynaptic differentiation. Nonphysiologic activation of Alk signaling also negatively regulates NMJ growth. Activation of Jeb-Alk signaling triggers the Ras-MAP kinase cascade in both pre- and postsynaptic compartments. These novel roles for Jeb-Alk signaling in the modulation of synaptic function and structure have potential implications for recently reported Alk functions in human addiction, retention of spatial memory, cognitive dysfunction in neurofibromatosis, and pathogenesis of amyotrophic lateral sclerosis.
Copyright © 2012 Wiley Periodicals, Inc.
1 Communities
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10 MeSH Terms
Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants.
Heuckmann JM, Balke-Want H, Malchers F, Peifer M, Sos ML, Koker M, Meder L, Lovly CM, Heukamp LC, Pao W, Küppers R, Thomas RK
(2012) Clin Cancer Res 18: 4682-90
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Anaplastic Lymphoma Kinase, Animals, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Crizotinib, HSP90 Heat-Shock Proteins, Humans, Kinesin, Lung Neoplasms, Mice, NIH 3T3 Cells, Oncogene Proteins, Fusion, Protein Kinase Inhibitors, Protein Stability, Protein-Tyrosine Kinases, Pyrazoles, Pyridines, Pyrimidines, Receptor Protein-Tyrosine Kinases, Signal Transduction
Show Abstract · Added September 3, 2013
PURPOSE - ALK rearrangement-positive lung cancers can be effectively treated with ALK inhibitors. However, the magnitude and duration of response is heterogeneous. In addition, acquired resistance limits the efficacy of ALK inhibitors, with most upfront resistance mechanisms being unknown.
EXPERIMENTAL DESIGN - By making use of the Ba/F3 cell line model, we analyzed the cytotoxic efficacy of ALK kinase inhibitors as a function of different EML4-ALK fusion variants v1, v2, v3a, and v3b as well as of three artificially designed EML4-ALK deletion constructs and the ALK fusion genes KIF5b-ALK and NPM1-ALK. In addition, the intracellular localization, the sensitivity to HSP90 inhibition and the protein stability of ALK fusion proteins were studied.
RESULTS - Different ALK fusion genes and EML4-ALK variants exhibited differential sensitivity to the structurally diverse ALK kinase inhibitors crizotinib and TAE684. In addition, differential sensitivity correlated with differences in protein stability in EML4-ALK-expressing cells. Furthermore, the sensitivity to HSP90 inhibition also varied depending on the ALK fusion partner but differed from ALK inhibitor sensitivity patterns. Finally, combining inhibitors of ALK and HSP90 resulted in synergistic cytotoxicity.
CONCLUSIONS - Our results might explain some of the heterogeneous responses of ALK-positive tumors to ALK kinase inhibition observed in the clinic. Thus, targeted therapy of ALK-positive lung cancer should take into account the precise ALK genotype. Furthermore, combining ALK and HSP90 inhibitors might enhance tumor shrinkage in EML4-ALK-driven tumors.
©2012 AACR.
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24 MeSH Terms
Chipping away at the lung cancer genome.
Pao W, Hutchinson KE
(2012) Nat Med 18: 349-51
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Anaplastic Lymphoma Kinase, Animals, Carcinoma, Non-Small-Cell Lung, Colorectal Neoplasms, Female, Humans, Kinesin, Lung Neoplasms, Male, Oncogene Proteins, Fusion, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases
Added September 3, 2013
0 Communities
2 Members
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16 MeSH Terms