Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model

Cancer Letters

Volumn 372, Issue 2, 2016, Pages 179-186

  Iyer, Radhika ^a   Wehrmann, Lea ^a   Golden, Rebecca L ^a   Naraparaju, Koumudi ^a   Croucher, Jamie L ^a   MacFarland, Suzanne P ^a   Guan, Peng ^a   Kolla, Venkatadri ^a   Wei, Ge ^b   Cam, Nicholas ^b   Li, Gang ^b   Hornby, Zachary ^b   Brodeur, Garrett M ^a,c  

^a CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^b Ignyta   (United States)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Entrectinib; Kinase inhibitor; Neuroblastoma; NTRK2; RXDX 101; TrkB

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR RECEPTOR; ENTRECTINIB; IRINOTECAN; TEMOZOLOMIDE; ANTINEOPLASTIC AGENT; BENZAMIDE DERIVATIVE; CAMPTOTHECIN; DACARBAZINE; INDAZOLE DERIVATIVE; MEMBRANE PROTEIN; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE; TROPOMYOSIN-RELATED KINASE-B, HUMAN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CONTROLLED STUDY; DRUG POTENTIATION; EVENT FREE SURVIVAL; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NEUROBLASTOMA; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SH SY5Y CELL LINE; TUMOR XENOGRAFT; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL PROLIFERATION; DOSE RESPONSE; DRUG EFFECTS; DRUG SCREENING; GENETIC TRANSFECTION; GENETICS; METABOLISM; NUDE MOUSE; PATHOLOGY; SIGNAL TRANSDUCTION; TIME FACTOR; TUMOR CELL LINE; TUMOR VOLUME;

ANIMALS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BENZAMIDES; CAMPTOTHECIN; CELL LINE, TUMOR; CELL PROLIFERATION; DACARBAZINE; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; INDAZOLES; MEMBRANE GLYCOPROTEINS; MICE, NUDE; NEUROBLASTOMA; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES; SIGNAL TRANSDUCTION; TIME FACTORS; TRANSFECTION; TUMOR BURDEN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84957619261     PISSN: 03043835     EISSN: 18727980     Source Type: Journal    
DOI: 10.1016/j.canlet.2016.01.018     Document Type: Article

References (89)

1. Lemmon M.A., Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010, 141:1117-1134.
2. McDonell L.M., Kernohan K.D., Boycott K.M., Sawyer S.L. Receptor tyrosine kinase mutations in developmental syndromes and cancer: two sides of the same coin. Hum. Mol. Genet 2015, 24:R60-R66.
3. Brodeur G.M., Iyer R., Croucher J.L., Zhuang T., Higashi M., Kolla V. Therapeutic targets for neuroblastomas. Expert Opin. Ther. Targets 2014, 18:277-292.
4. Brodeur G.M., Minturn J.E., Ho R., Simpson A.M., Iyer R., Varela C.R., et al. Trk receptor expression and inhibition in neuroblastomas. Clin. Cancer Res 2009, 15:3244-3250.
5. Thiele C.J., Li Z., McKee A.E. On Trk - the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin. Cancer Res 2009, 15:5962-5967.
6. Kogner P., Barbany G., Dominici C., Castello M.A., Raschella G., Persson H. Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis. Cancer Res 1993, 53:2044-2050.
7. Nakagawara A., Arima M., Azar C.G., Scavarda N.J., Brodeur G.M. Inverse relationship between trk expression and N-myc amplification in human neuroblastomas. Cancer Res 1992, 52:1364-1368.
8. Nakagawara A., Azar C.G., Scavarda N.J., Brodeur G.M. Expression and function of TRK-B and BDNF in human neuroblastomas. Mol. Cell. Biol 1994, 14:759-767.
9. Nakagawara A., Arima-Nakagawara M., Scavarda N.J., Azar C.G., Cantor A.B., Brodeur G.M. Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N. Engl. J. Med 1993, 328:847-854.
10. Nakagawara A., Brodeur G.M. Role of neurotrophins and their receptors in human neuroblastomas: a primary culture study. Eur. J. Cancer 1997, 33:2050-2053.
11. Suzuki T., Bogenmann E., Shimada H., Stram D., Seeger R.C. Lack of high-affinity nerve growth factor receptors in aggressive neuroblastomas. J. Natl. Cancer Inst 1993, 85:377-384.
12. Acheson A., Conover J.C., Fandl J.P., DeChiara T.M., Russell M., Thadani A., et al. A BDNF autocrine loop in adult sensory neurons prevents cell death [see comments]. Nature 1995, 374:450-453.
13. Ho R., Eggert A., Hishiki T., Minturn J.E., Ikegaki N., Foster P., et al. Resistance to chemotherapy mediated by TrkB in neuroblastomas. Cancer Res 2002, 62:6462-6466.
14. Matsumoto K., Wada R.K., Yamashiro J.M., Kaplan D.R., Thiele C.J. Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res 1995, 55:1798-1806.
15. Nakamura K., Martin K.C., Jackson J.K., Beppu K., Woo C.W., Thiele C.J. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res 2006, 66:4249-4255.
16. Ivanov S.V., Panaccione A., Brown B., Guo Y., Moskaluk C.A., Wick M.J., et al. TrkC signaling is activated in adenoid cystic carcinoma and requires NT-3 to stimulate invasive behavior. Oncogene 2013, 32:3698-3710.
17. Lee J., Jiffar T., Kupferman M.E. A novel role for BDNF-TrkB in the regulation of chemotherapy resistance in head and neck squamous cell carcinoma. PLoS ONE 2012, 7:e30246.
18. Ng Y.K., Wong E.Y., Lau C.P., Chan J.P., Wong S.C., Chan A.S., et al. K252a induces anoikis-sensitization with suppression of cellular migration in Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma cells. Invest. New Drugs 2012, 30:48-58.
19. Ryden M., Sehgal R., Dominici C., Schilling F.H., Ibanez C.F., Kogner P. Expression of mRNA for the neurotrophin receptor trkC in neuroblastomas with favourable tumour stage and good prognosis. Br. J. Cancer 1996, 74:773-779.
20. Yamashiro D.J., Liu X.G., Lee C.P., Nakagawara A., Ikegaki N., McGregor L.M., et al. Expression and function of Trk-C in favourable human neuroblastomas. Eur. J. Cancer 1997, 33:2054-2057.
21. Yamashiro D.J., Nakagawara A., Ikegaki N., Liu X.G., Brodeur G.M. Expression of TrkC in favorable human neuroblastomas. Oncogene 1996, 12:37-41.
22. Chen Z., Akbay E., Mikse O., Tupper T., Cheng K., Wang Y., et al. Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin. Cancer Res 2014, 20:1204-1211.
23. Vaishnavi A., Le A.T., Doebele R.C. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015, 5:25-34.
24. Evans A.E., Kisselbach K.D., Liu X., Eggert A., Ikegaki N., Camoratto A.M., et al. Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB. Med. Pediatr. Oncol 2001, 36:181-184.
25. Evans A.E., Kisselbach K.D., Yamashiro D.J., Ikegaki N., Camoratto A.M., Dionne C.A., et al. Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and medulloblastoma xenografts. Clin. Cancer Res 1999, 5:3594-3602.
26. Iyer R., Evans A.E., Qi X., Ho R., Minturn J.E., Zhao H., et al. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma. Clin. Cancer Res 2010, 16:1478-1485.
27. Minturn J.E., Evans A.E., Villablanca J.G., Yanik G.A., Park J.R., Shusterman S., et al. Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study. Cancer Chemother. Pharmacol 2011, 68:1057-1065.
28. Croucher J.L., Iyer R., Li N., Molteni V., Loren J., Gordon W.P., et al. TrkB inhibition by GNF-4256 slows growth and enhances chemotherapeutic efficacy in neuroblastoma xenografts. Cancer Chemother. Pharmacol 2015, 75:131-141.
29. Iyer R., Varela C.R., Minturn J.E., Ho R., Simpson A.M., Light J.E., et al. AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts. Cancer Chemother. Pharmacol 2012, 70:477-486.
30. Vichai V., Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc 2006, 1:1112-1116.
31. Brodeur G.M., Maris J.M. Neuroblastoma. Principles and Practice of Pediatric Oncology 2010, 886-922. Lippincott, Williams and Wilkins, Philadelphia. P.A. Pizzo, D.G. Poplack (Eds.).
32. Maris J.M., Hogarty M.D., Bagatell R., Cohn S.L. Neuroblastoma. Lancet 2007, 369:2106-2120.
33. Modak S., Cheung N.K. Neuroblastoma: therapeutic strategies for a clinical enigma. Cancer Treat. Rev 2010, 36:307-317.
34. Eggert A., Grotzer M.A., Ikegaki N., Liu X.G., Evans A.E., Brodeur G.M. Expression of the neurotrophin receptor TrkA down-regulates expression and function of angiogenic stimulators in SH-SY5Y neuroblastoma cells. Cancer Res 2002, 62:1802-1808.
35. Lucarelli E., Kaplan D., Thiele C.J. Activation of trk-A but not trk-B signal transduction pathway inhibits growth of neuroblastoma cells. Eur. J. Cancer 1997, 33:2068-2070.
36. Jaboin J., Kim C.J., Kaplan D.R., Thiele C.J. Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3'-kinase pathway. Cancer Res 2002, 62:6756-6763.
37. Rolfo C., Ruiz R., Giovannetti E., Gil-Bazo I., Russo A., Passiglia F., et al. Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin. Investig. Drugs 2015, 24:1493-1500.
38. Amatu A., Somaschini A., Cerea G., Bosotti R., Valtorta E., Buonandi P., et al. Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer. Br. J. Cancer 2015, 113:1730-1734.
39. Aveic S., Pantile M., Seydel A., Esposito M.R., Zanon C., Li G., et al. Combating autophagy is a strategy to increase cytotoxic effects of novel ALK inhibitor entrectinib in neuroblastoma cells. Oncotarget 2015, 10.18632/oncotarget.6778.
40. Awad M.M., Shaw A.T. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin. Adv. Hematol. Oncol 2014, 12:429-439.
41. Iragavarapu C., Mustafa M., Akinleye A., Furqan M., Mittal V., Cang S., et al. Novel ALK inhibitors in clinical use and development. J Hematol Oncol 2015, 8:17.
42. Lee J., Kim H.C., Hong J.Y., Wang K., Kim S.Y., Jang J., et al. Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening. Oncotarget 2015, 6:24320-24332.
43. Chen Y., Takita J., Choi Y.L., Kato M., Ohira M., Sanada M., et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 2008, 455:971-974.
44. George R.E., Sanda T., Hanna M., Frohling S., Luther W., Zhang J., et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature 2008, 455:975-978.
45. Janoueix-Lerosey I., Lequin D., Brugieres L., Ribeiro A., de Pontual L., Combaret V., et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 2008, 455:967-970.
46. Mosse Y.P., Laudenslager M., Longo L., Cole K.A., Wood A., Attiyeh E.F., et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 2008, 455:930-935.
47. Azarova A.M., Gautam G., George R.E. Emerging importance of ALK in neuroblastoma. Semin. Cancer Biol 2011, 21:267-275.
48. Carpenter E.L., Mosse Y.P. Targeting ALK in neuroblastoma - preclinical and clinical advancements. Nat. Rev. Clin. Oncol 2012, 9:391-399.
49. Berry T., Luther W., Bhatnagar N., Jamin Y., Poon E., Sanda T., et al. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell 2012, 22:117-130.
50. Heuckmann J.M., Holzel M., Sos M.L., Heynck S., Balke-Want H., Koker M., et al. ALK mutations conferring differential resistance to structurally diverse ALK inhibitors. Clin. Cancer Res 2011, 17:7394-7401.
51. Sasaki T., Okuda K., Zheng W., Butrynski J., Capelletti M., Wang L., et al. The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res 2010, 70:10038-10043.
52. De Braud F.G., Niger M., Damian S., Bardazza B., Martinetti A., Pelosi G., et al. Alka-372-001: First-in-human, phase I study of entrectinib - an oral pan-trk, ROS1, and ALK inhibitor - in patients with advanced solid tumors with relevant molecular alterations, ASCO Annual Meeting, Chicago, IL. J. Clin. Oncol 2015, (Suppl). Abstract 2517.
53. Patel M.R., ABauer T.M., Liu S.V., Drilon A.E., Wheler J.J., Shaw A.T., et al. STARTRK-1: Phase 1/2a study of entrectinib, an oral Pan-Trk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alterations, ASCO Annual Meeting, Chicago, IL. J. Clin. Oncol 2015, (Suppl). Abstract 2596.
54. Eggert A., Grotzer M.A., Ikegaki N., Zhao H., Cnaan A., Brodeur G.M., et al. Expression of the neurotrophin receptor TrkB is associated with unfavorable outcome in Wilms' tumor. J. Clin. Oncol 2001, 19:689-696.
55. Chou T.T., Trojanowski J.Q., Lee V.M. Neurotrophin signal transduction in medulloblastoma. J. Neurosci. Res 1997, 49:522-527.
56. Grotzer M.A., Janss A.J., Fung K., Biegel J.A., Sutton L.N., Rorke L.B., et al. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J. Clin. Oncol 2000, 18:1027-1035.
57. Kim J.Y., Sutton M.E., Lu D.J., Cho T.A., Goumnerova L.C., Goritchenko L., et al. Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res 1999, 59:711-719.
58. Segal R.A., Goumnerova L.C., Kwon Y.K., Stiles C.D., Pomeroy S.L. Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc. Natl. Acad. Sci. U.S.A. 1994, 91:12867-12871.
59. Nogueira E., Navarro S., Pellin A., Llombart-Bosch A. Activation of TRK genes in Ewing's sarcoma. Trk A receptor expression linked to neural differentiation. Diagn. Mol. Pathol 1997, 6:10-16.
60. Knezevich S.R., McFadden D.E., Tao W., Lim J.F., Sorensen P.H. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat. Genet 1998, 18:184-187.
61. Liu Q., Schwaller J., Kutok J., Cain D., Aster J.C., Williams I.R., et al. Signal transduction and transforming properties of the TEL-TRKC fusions associated with t(12;15)(p13;q25) in congenital fibrosarcoma and acute myelogenous leukemia. EMBO J. 2000, 19:1827-1838.
62. Rubin B.P., Chen C.J., Morgan T.W., Xiao S., Grier H.E., Kozakewich H.P., et al. Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am. J. Pathol 1998, 153:1451-1458.
63. Jin W., Kim G.M., Kim M.S., Lim M.H., Yun C., Jeong J., et al. TrkC plays an essential role in breast tumor growth and metastasis. Carcinogenesis 2010, 31:1939-1947.
64. Lagadec C., Meignan S., Adriaenssens E., Foveau B., Vanhecke E., Romon R., et al. TrkA overexpression enhances growth and metastasis of breast cancer cells. Oncogene 2009, 28:1960-1970.
65. Dolle L., Adriaenssens E., El Yazidi-Belkoura I., Le Bourhis X., Nurcombe V., Hondermarck H. Nerve growth factor receptors and signaling in breast cancer. Curr. Cancer Drug Targets 2004, 4:463-470.
66. Dolle L., El Yazidi-Belkoura I., Adriaenssens E., Nurcombe V., Hondermarck H. Nerve growth factor overexpression and autocrine loop in breast cancer cells. Oncogene 2003, 22:5592-5601.
67. Tognon C., Knezevich S.R., Huntsman D., Roskelley C.D., Melnyk N., Mathers J.A., et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2002, 2:367-376.
68. Euhus D.M., Timmons C.F., Tomlinson G.E. ETV6-NTRK3 - Trk-ing the primary event in human secretory breast cancer. Cancer Cell 2002, 2:347-348.
69. Descamps S., Pawlowski V., Revillion F., Hornez L., Hebbar M., Boilly B., et al. Expression of nerve growth factor receptors and their prognostic value in human breast cancer. Cancer Res 2001, 61:4337-4340.
70. Festuccia C., Muzi P., Gravina G.L., Millimaggi D., Speca S., Dolo V., et al. Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro. Int. J. Oncol 2007, 30:193-200.
71. Weeraratna A.T., Dalrymple S.L., Lamb J.C., Denmeade S.R., Miknyoczki S., Dionne C.A., et al. Pan-trk inhibition decreases metastasis and enhances host survival in experimental models as a result of its selective induction of apoptosis of prostate cancer cells. Clin. Cancer Res 2001, 7:2237-2245.
72. Weeraratna A.T., Arnold J.T., George D.J., DeMarzo A., Isaacs J.T. Rational basis for Trk inhibition therapy for prostate cancer. Prostate 2000, 45:140-148.
73. Dionne C.A., Camoratto A.M., Jani J.P., Emerson E., Neff N., Vaught J.L., et al. Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587). Clin. Cancer Res 1998, 4:1887-1898.
74. Pflug B.R., Dionne C., Kaplan D.R., Lynch J., Djakiew D. Expression of a Trk high affinity nerve growth factor receptor in the human prostate. Endocrinology 1995, 136:262-268.
75. Sartore-Bianchi A., Ardini E., Bosotti R., Amatu A., Valtorta E., Somaschini A., et al. Sensitivity to entrectinib associated with a novel LMNA-NTRK1 gene fusion in metastatic colorectal cancer. J. Natl. Cancer Inst 2016, 108.
76. Russo M., Misale S., Wei G., Siravegna G., Crisafulli G., Lazzari L., et al. Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov 2015, 6:36-44.
77. Lee S.J., Li G.G., Kim S.T., Hong M.E., Jang J., Yoon N., et al. NTRK1 rearrangement in colorectal cancer patients: evidence for actionable target using patient-derived tumor cell line. Oncotarget 2015, 6:39028-39035.
78. Sasahira T., Ueda N., Kurihara M., Matsushima S., Ohmori H., Fujii K., et al. Tropomyosin receptor kinases B and C are tumor progressive and metastatic marker in colorectal carcinoma. Hum. Pathol 2013, 44:1098-1106.
79. Fujikawa H., Tanaka K., Toiyama Y., Saigusa S., Inoue Y., Uchida K., et al. High TrkB expression levels are associated with poor prognosis and EMT induction in colorectal cancer cells. J. Gastroenterol 2012, 47:775-784.
80. Yu Y., Zhang S., Wang X., Yang Z., Ou G. Overexpression of TrkB promotes the progression of colon cancer. APMIS 2010, 118:188-195.
81. Sclabas G.M., Fujioka S., Schmidt C., Li Z., Frederick W.A., Yang W., et al. Overexpression of tropomysin-related kinase B in metastatic human pancreatic cancer cells. Clin. Cancer Res 2005, 11:440-449.
82. Miknyoczki S.J., Wan W., Chang H., Dobrzanski P., Ruggeri B.A., Dionne C.A., et al. The neurotrophin-trk receptor axes are critical for the growth and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice. Clin. Cancer Res 2002, 8:1924-1931.
83. Schneider M.B., Standop J., Ulrich A., Wittel U., Friess H., Andren-Sandberg A., et al. Expression of nerve growth factors in pancreatic neural tissue and pancreatic cancer. J. Histochem. Cytochem 2001, 49:1205-1210.
84. Sakamoto Y., Kitajima Y., Edakuni G., Sasatomi E., Mori M., Kitahara K., et al. Expression of Trk tyrosine kinase receptor is a biologic marker for cell proliferation and perineural invasion of human pancreatic ductal adenocarcinoma. Oncol. Rep 2001, 8:477-484.
85. Miknyoczki S.J., Lang D., Huang L., Klein-Szanto A.J., Dionne C.A., Ruggeri B.A. Neurotrophins and Trk receptors in human pancreatic ductal adenocarcinoma: expression patterns and effects on in vitro invasive behavior. Int. J. Cancer 1999, 81:417-427.
86. Farago A.F., Le L.P., Zheng Z., Muzikansky A., Drilon A., Patel M., et al. Durable clinical response to entrectinib in NTRK1-rearranged non-small cell lung cancer. J. Thorac. Oncol 2015, 10:1670-1674.
87. Harada T., Yatabe Y., Takeshita M., Koga T., Yano T., Wang Y., et al. Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin. Cancer Res 2011, 17:2638-2645.
88. Ricci A., Greco S., Mariotta S., Felici L., Bronzetti E., Cavazzana A., et al. Neurotrophins and neurotrophin receptors in human lung cancer. Am. J. Respir. Cell Mol. Biol 2001, 25:439-446.
89. Vaishnavi A., Capelletti M., Le A.T., Kako S., Butaney M., Ercan D., et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat. Med 2013, 19:1469-1472.