Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 12

Publication Record

Connections

Impact of EML4-ALK Variant on Resistance Mechanisms and Clinical Outcomes in ALK-Positive Lung Cancer.
Lin JJ, Zhu VW, Yoda S, Yeap BY, Schrock AB, Dagogo-Jack I, Jessop NA, Jiang GY, Le LP, Gowen K, Stephens PJ, Ross JS, Ali SM, Miller VA, Johnson ML, Lovly CM, Hata AN, Gainor JF, Iafrate AJ, Shaw AT, Ou SI
(2018) J Clin Oncol 36: 1199-1206
MeSH Terms: Adult, Aged, Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung, Crizotinib, Drug Resistance, Neoplasm, Female, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Oncogene Proteins, Fusion, Prognosis, Protein Kinase Inhibitors, Retrospective Studies, Treatment Outcome, Young Adult
Show Abstract · Added September 10, 2020
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
0 Communities
1 Members
0 Resources
MeSH Terms
Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer.
Li C, Singh B, Graves-Deal R, Ma H, Starchenko A, Fry WH, Lu Y, Wang Y, Bogatcheva G, Khan MP, Milne GL, Zhao S, Ayers GD, Li N, Hu H, Washington MK, Yeatman TJ, McDonald OG, Liu Q, Coffey RJ
(2017) Proc Natl Acad Sci U S A 114: E2852-E2861
MeSH Terms: Animals, Antineoplastic Agents, Immunological, Cell Culture Techniques, Cell Line, Tumor, Cetuximab, Colorectal Neoplasms, Crizotinib, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Hydroxyprostaglandin Dehydrogenases, Mice, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyrazoles, Pyridines, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Tissue Array Analysis, Versicans, Xenograft Model Antitumor Assays
Show Abstract · Added May 3, 2017
We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated in 3D in type-I collagen. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained their parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), the EGFR-neutralizing monoclonal antibody, cetuximab, strongly inhibited growth of CC, whereas SC was resistant to growth inhibition, and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. To further characterize these two lines, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most up-regulated genes in CC was the tumor suppressor , and the most up-regulated gene in SC was () in 3D and xenografts. Analysis of a CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic strategies and disease-relevant genes in CRC and possibly other solid tumors.
0 Communities
3 Members
0 Resources
22 MeSH Terms
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.
0 Communities
1 Members
0 Resources
34 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.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions.
Lovly CM, Gupta A, Lipson D, Otto G, Brennan T, Chung CT, Borinstein SC, Ross JS, Stephens PJ, Miller VA, Coffin CM
(2014) Cancer Discov 4: 889-95
MeSH Terms: Anaplastic Lymphoma Kinase, Biomarkers, Tumor, Child, Crizotinib, Humans, Inflammation, Male, Neoplasms, Muscle Tissue, Oncogene Proteins, Fusion, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Pyrazoles, Pyridines, Receptor Protein-Tyrosine Kinases, Receptor, Platelet-Derived Growth Factor beta
Show Abstract · Added September 10, 2020
UNLABELLED - Inflammatory myofibroblastic tumor (IMT) is a neoplasm that typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase (ALK) rearrangements, no therapeutic targets have been identified in ALK-negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evaluated harbored kinase fusions involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.
SIGNIFICANCE - Our study describes the most comprehensive genomics-based evaluation of IMT to date. Because there is no "standard-of-care" therapy for IMT, the identification of actionable genomic alterations, in addition to ALK, is expected to redefine management strategies for patients with this disease.
©2014 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
MeSH Terms
A patient with metastatic lung adenocarcinoma harboring concurrent EGFR L858R, EGFR germline T790M, and PIK3CA mutations: the challenge of interpreting results of comprehensive mutational testing in lung cancer.
Lammers PE, Lovly CM, Horn L
(2014) J Natl Compr Canc Netw 12: 6-11; quiz 11
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Aged, Carcinoma, Non-Small-Cell Lung, Class I Phosphatidylinositol 3-Kinases, Crizotinib, Drug Resistance, Neoplasm, ErbB Receptors, Erlotinib Hydrochloride, Humans, Lung Neoplasms, Male, Mutation, Phosphatidylinositol 3-Kinases, Precision Medicine, Pyrazoles, Pyridines, Quinazolines, Treatment Outcome
Show Abstract · Added June 26, 2014
Mutational testing has moved to the forefront as an integral component in the management of patients with non-small cell lung cancer (NSCLC). Currently 3 targeted therapies (erlotinib, afatinib, and crizotinib) are approved by the FDA to treat patients with specific genetic abnormalities in NSCLC. As mutational screening expands to include a greater number of genes, the results will become more difficult to interpret, particularly if mutations are found in multiple genes or genes that are not actionable at the time of testing. This case report summarizes the diagnosis and treatment of a patient with NSCLC that harbored multiple potentially targetable driver mutations. It also discusses the current NCCN Clinical Practice Guidelines in Oncology for mutational testing in NSCLC and the inherent difficulties with interpreting mutational results when multiple mutations are found in a single gene or across multiple genes.
0 Communities
2 Members
0 Resources
19 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.
0 Communities
2 Members
0 Resources
23 MeSH Terms
Crizotinib induces PUMA-dependent apoptosis in colon cancer cells.
Zheng X, He K, Zhang L, Yu J
(2013) Mol Cancer Ther 12: 777-86
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Cell Line, Tumor, Colonic Neoplasms, Crizotinib, Drug Synergism, Female, Gefitinib, Gene Expression Regulation, Neoplastic, Humans, Mice, Niacinamide, Phenylurea Compounds, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Pyrazoles, Pyridines, Quinazolines, Sorafenib, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Show Abstract · Added July 28, 2015
Oncogenic alterations in MET or anaplastic lymphoma kinase (ALK) have been identified in a variety of human cancers. Crizotinib (PF02341066) is a dual MET and ALK inhibitor and approved for the treatment of a subset of non-small cell lung carcinoma and in clinical development for other malignancies. Crizotinib can induce apoptosis in cancer cells, whereas the underlying mechanisms are not well understood. In this study, we found that crizotinib induces apoptosis in colon cancer cells through the BH3-only protein PUMA. In cells with wild-type p53, crizotinib induces rapid induction of PUMA and Bim accompanied by p53 stabilization and DNA damage response. The induction of PUMA and Bim is mediated largely by p53, and deficiency in PUMA or p53, but not Bim, blocks crizotinib-induced apoptosis. Interestingly, MET knockdown led to selective induction of PUMA, but not Bim or p53. Crizotinib also induced PUMA-dependent apoptosis in p53-deficient colon cancer cells and synergized with gefitinib or sorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and therapeutic responses to crizotinib in xenograft models. These results establish a critical role of PUMA in mediating apoptotic responses of colon cancer cells to crizotinib and suggest that mechanisms of oncogenic addiction to MET/ALK-mediated survival may be cell type-specific. These findings have important implications for future clinical development of crizotinib.
©2013 AACR
0 Communities
1 Members
0 Resources
23 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.
0 Communities
3 Members
0 Resources
24 MeSH Terms
Escaping ALK inhibition: mechanisms of and strategies to overcome resistance.
Lovly CM, Pao W
(2012) Sci Transl Med 4: 120ps2
MeSH Terms: Anaplastic Lymphoma Kinase, Crizotinib, Humans, Lung Neoplasms, Protein Kinase Inhibitors, Pyrazoles, Pyridines, Receptor Protein-Tyrosine Kinases
Show Abstract · Added September 3, 2013
Mutated anaplastic lymphoma kinase (ALK) drives the development of multiple tumor types, and ALK tyrosine kinase inhibitors such as crizotinib have been validated as targeted therapeutics. Unfortunately, as with other oncogene-driven tumors, therapeutic resistance invariably develops. In Science Translational Medicine, two recent studies provide new insight into mechanisms of resistance to ALK tyrosine kinase inhibitors and possible strategies to overcome this resistance.
0 Communities
3 Members
0 Resources
8 MeSH Terms