ライフサイエンスコーパス: ALK

1 ALK receptor tyrosine kinase has been shown to be a ther

2 ALK was first identified in a subset of T-cell lymphomas

3 ALK(F1174L) induces NEFM, RET, and VACHT and results in

4 ALK, ROS1 and RET gene fusions are important predictive

5 ALK-rearranged non-small-cell lung cancer (NSCLC) is sen

6 r-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients.

7 as reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of

8 rating keratoplasty (date range, 1992-2013), ALK (date range, 2002-2013), and Descemet's stripping au

9 ell lung cancer line (H3122) to a panel of 4 ALK TKIs, and performed a collateral sensitivity analysi

10 TGF-betaRI) (activin receptor-like kinase 5 [ALK-5]) and TGF-beta receptor II (TGF-betaRII).

11 naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients.

12 as reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163

13 Aberrant ALK-FISH patterns were examined in CTCs using immunofluo

14 The aberrant ALK expression in nonneural cells results from chromosom

15 circulating tumor cells (CTC) with aberrant ALK-FISH patterns [ALK-rearrangement, ALK-copy number ga

16 f overexpression of MYCN, MYC, and activated ALK, alone and in combination.

17 es and xenograft models expressing activated ALK.

18 xpectedly, long-term expression of activated ALK(F1174L) leads to cell-cycle arrest and promotes diff

19 Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in criz

20 lation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than

21 racranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CN

22 istance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC.

23 agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previo

24 treatment option for patients with advanced ALK-rearranged NSCLC.

25 ersus chemotherapy in patients with advanced ALK-rearranged NSCLC.

26 ed to glaucoma was 1.0% after EK, 2.1% after ALK, and 3.6% after PK (P = 0.036).

27 ted bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect

28 tor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibi

29 ents, demonstrates striking efficacy against ALK-rearranged NB.

30 All ALK inhibitor resistant cell lines displayed significant

31 To address this, we evolved resistance in an ALK rearranged non-small cell lung cancer line (H3122) t

32 CXCL1 in vivo was inhibited by GDF-15 in an ALK-5 and TGF-betaRII dependent way.

33 bly, TGF-beta2 controls furin activity in an ALK-5-dependent manner involving the ERK/MAPK pathway.

34 Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the tre

35 equencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation.

36 d that gene mutations for EGFR (P = .02) and ALK (P < .001) were associated with cancer diagnosis at

37 tin/DNA damage regulator mutations (21%) and ALK translocation (2%) distinguish additional cases.

38 regulated pathways involving KRAS, BRCA1 and ALK, for example.

39 he DS-GPA index plus 2 new factors: EGFR and ALK alterations in patients with adenocarcinoma (mutatio

40 es, intrathoracic nodal status, and EGFR and ALK status.

41 dulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mu

42 reens in the setting of BRAF, MEK, EGFR, and ALK inhibition.

43 nhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells.

44 le-associated protein-like 4 (EML4) gene and ALK lead to an inversion of genetic material that forms

45 growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively.

46 Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncoge

47 trate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred

48 gh rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal gro

49 LC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior ther

50 progression to NB, but the role of MYCN and ALK in tumorigenesis is still poorly understood.

51 st proliferation is maintained when MYCN and ALK(F1174L) are coexpressed.

52 ighly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed aft

53 naplastic lymphoma kinase (ALK)-positive and ALK-negative entities.

54 ritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC.

55 ilure of first line ALK TKI therapy, another ALK TKI is administered, though collateral sensitivity i

56 nd therapeutic effectiveness of FDA-approved ALK inhibitors indicated that EML4-ALK is a driving fact

57 egions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1 The over 1,000 genetic alter

58 pies, towards oncogenic driver genes such as ALK-EML4, to overcome the inevitable resistance that dev

59 ell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking

60 d 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, effici

61 novel ALK fusions in a neuroblastoma (BEND5-ALK) and an astrocytoma (PPP1CB-ALK), novel BRAF fusions

62 b has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patient

63 ess whole-body activity of ceritinib in both ALK inhibitor-pretreated and ALK inhibitor-naive patient

64 al for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.

65 Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected

66 olled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), cri

67 Combining ALK inhibition with other novel therapeutic modalities s

68 Rac1 have nonredundant roles in controlling ALK-rearranged lymphoma survival and morphology but are

69 lines indistinguishable from patient-derived ALK+ ALCL.

70 Although not dominant, ALK-CNG has been reported to be one of the mechanisms of

71 oncogenes, including BRAF, NRAS, NF1, EGFR, ALK, TERT, and APC.

72 ical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1.

73 reflex molecular profile, includingKRAS,EGFR,ALK,BRAF,HER2,RET,MET, andROS, did not reveal an actiona

74 arcinoma (without positive markers, eg, EGFR/ALK /ROS1), if the patient has high programmed death lig

75 t one dose of study treatment and had either ALK or ROS1 rearrangement).

76 EML4-ALK induced hypoxia-independent but glucose-dependent ac

77 tions, and 1 MET mutation, as well as 1 EML4-ALK gene fusion and 1 KIF5B-RET gene fusion.

78 d the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacte

79 The link from EML4-ALK to HK2 upregulation is essential for a high rate of

80 graphy imaging of xenografts grown from EML4-ALK-positive NSCLC cells.

81 that forms the non-natural gene fusion EML4-ALK encoding a constitutively active tyrosine kinase tha

82 nical study showed that NSCLC harboring EML4-ALK rearrangements displayed higher glucose metabolism c

83 ascade to enhance glucose metabolism in EML4-ALK-positive NSCLC.

84 tein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein is found in approximately 3-7% of no

85 Our data reveal a novel EML4-ALK-HIF1alpha-HK2 cascade to enhance glucose metabolism

86 rate of glycolysis and proliferation of EML4-ALK-rearranged NSCLC cells.

87 -approved ALK inhibitors indicated that EML4-ALK is a driving factor of lung tumorigenesis.

88 urrent work, we presented evidence that EML4-ALK is coupled to overexpression of hexokinase II (HK2),

89 We also resolve the structure of the EML4-ALK gene fusion in the NCI-H2228 cancer cell line using

90 The EML4-ALK-mediated upregulation of HIF1alpha, HK2 and glycolyt

91 higher glucose metabolism compared with EML4-ALK-negative NSCLC.

92 We then evaluated ALK-inhibitor sensitivities after drug holidays of varyi

93 However, aberrantly expressed ALK is involved in the pathogenesis of diverse malignanc

94 inib, are active against NB cells expressing ALK(F1174L).

95 he discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in

96 LC patients treated with crizotinib as first ALK inhibitor were recruited prospectively.

97 activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resista

98 For ALK-positive patients, the proportion of patients who ac

99 t extravasation of neutrophils deficient for ALK-5 or TGF-betaRII was strongly increased in the inter

100 he clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histolo

101 y a differentiated phenotype but differ from ALK-expressing neurons by the upregulation of SKP2, CCNA

102 Patients with brain metastases from ALK-rearranged NSCLC treated with radiotherapy (SRS and/

103 al of 90 patients with brain metastases from ALK-rearranged NSCLC were identified from six institutio

104 her NGS fusion panel) to those obtained from ALK, ROS1 and RET FISH on 51 clinical specimens.

105 ns [ALK-rearrangement, ALK-copy number gain (ALK-CNG)] monitored on crizotinib could predict progress

106 tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-0646

107 available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomi

108 Germline ALK activating mutations are responsible for the majorit

109 ose of ceritinib 750 mg/day, of whom 246 had ALK-rearranged NSCLC.

110 TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in

111 non-small cell lung cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy again

112 done before lorlatinib treatment to identify ALK resistance mutations.

113 ype I binding mode, but only limited type II ALK structural studies are available.

114 In ALK-rearranged anaplastic large cell lymphoma (ALCL), a

115 r-naive patients and 8.3 months (6.8-9.7) in ALK inhibitor-pretreated patients.

116 r-naive patients and 6.9 months (5.6-8.7) in ALK inhibitor-pretreated patients.

117 ovo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the

118 dictive biomarker for crizotinib efficacy in ALK-rearranged NSCLC patients.

119 discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer ou

120 acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to over

121 survival was 18.4 months (95% CI 11.1-NE) in ALK inhibitor-naive patients and 6.9 months (5.6-8.7) in

122 0 months (95% CI 11.3-non-estimable [NE]) in ALK inhibitor-naive patients and 8.3 months (6.8-9.7) in

123 elevant example of this phenomenon occurs in ALK-positive non-small cell lung cancer, where targeted

124 wever, their role and possible redundancy in ALK-driven lymphoma development in vivo are still undete

125 udy shows how the evolution of resistance in ALK-positive lung cancer is a dynamic process through ti

126 We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed

127 de of clinical response are unpredictable in ALK-rearranged non-small cell lung cancer (NSCLC) patien

128 age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to

129 sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invar

130 nd 14 patients with metastatic or inoperable ALK-positive IMT received crizotinib orally twice daily.

131 Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against A

132 udy in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centre

133 s aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib.

134 of broad inhibition of activin-like kinase (ALK) receptors 4/5/7 recognizing TGF-beta, activin, grow

135 angements in the anaplastic lymphoma kinase (ALK) gene associated with ALK-positive non-small-cell lu

136 positive for an anaplastic lymphoma kinase (ALK) gene rearrangement using fluorescence in situ hybri

137 Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-sm

138 rally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability.

139 next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour effic

140 Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only li

141 lopment of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action.

142 Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase physiologically expre

143 Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the d

144 d with activated anaplastic lymphoma kinase (ALK) is sufficient to induce neuroblastoma (NB) in mouse

145 T cells that are anaplastic lymphoma kinase (ALK) negative and CD30 positive.

146 FR mutations and anaplastic lymphoma kinase (ALK) translocations.

147 ncies, including anaplastic lymphoma kinase (ALK)(-) anaplastic large cell lymphomas (ALCLs).

148 cally related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial invest

149 al activation of anaplastic lymphoma kinase (ALK), which promotes progression to NB, but the role of

150 ncludes systemic anaplastic lymphoma kinase (ALK)-positive and ALK-negative entities.

151 o had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib de

152 s with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is no

153 st patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearrange

154 Currently, after failure of first line ALK TKI therapy, another ALK TKI is administered, though

155 zotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of

156 ombinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K

157 astic large cell lymphoma (ALCL) morphology (ALK+ ALCL), the vast majority of which harbor the well-c

158 assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplasti

159 umors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models.

160 lular and molecular effects elicited by MYCN/ALK cooperation, we used cultures of chick sympathetic n

161 Together, our results characterize MYCN/ALK cooperation leading to neuroblast proliferation and

162 Combined MYCN/ALK(F1174L) expression allows long-term proliferation an

163 SKP2 in the maintained proliferation of MYCN/ALK(F1174L) neuroblasts.

164 neuroblast proliferation downstream of MYCN/ALK, which may represent an early step toward tumorigene

165 Proliferating MYCN/ALK(F1174L) neuroblasts display a differentiated phenoty

166 with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC.

167 ase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-

168 displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in bo

169 Here we show that a new ALK inhibitor AZD3463 effectively suppressed the prolife

170 Thirty-nine ALK-rearranged NSCLC patients treated with crizotinib as

171 tablet (MK-8237; Merck & Co, Kenilworth, NJ/ALK-Abello, Horsholm, Denmark) has demonstrated benefici

172 hylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode.

173 We identified novel ALK fusions in a neuroblastoma (BEND5-ALK) and an astroc

174 r the well-characterized nucleophosmin (NPM)-ALK fusion protein.

175 NPM-ALK co-opts several intracellular signal transduction pa

176 NPM-ALK-deregulated kinase activity drives several pathways

177 In addition, NPM-ALK uses epigenetic silencing mechanisms to downregulate

178 NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus.

179 option in cells that become resistant by NPM-ALK amplification.

180 Many genes and proteins modulated by NPM-ALK are also involved in evasion of antitumor immune res

181 el actin signaling pathways regulated by NPM-ALK, a comprehensive phosphoproteome analysis of ALCL ce

182 yndrome protein (WASp) were regulated by NPM-ALK.

183 -rearrangement, which is bypassed in CD4/NPM-ALK transgenic mice following Notch1 expression.

184 Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinas

185 Importantly, NPM-ALK is capable of transforming primary human CD4(+) T ce

186 that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytopla

187 hese findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncog

188 performed in the presence or absence of NPM-ALK activity.

189 Levels of NPM-ALK decreased during therapy in most patients with ALCL.

190 tudies evaluated the serial detection of NPM-ALK fusion transcripts in patients with ALCL.

191 ical studies indicate that inhibition of NPM-ALK induces long-lasting complete remissions in a large

192 Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdow

193 1 single deletions, completely prevented NPM-ALK lymphoma dissemination in vivo.

194 23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase).

195 Here we show that NPM-ALK phosphorylates WASp at its known activation site (Y2

196 Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 hetero

197 that WASp is a central component of the NPM-ALK-dependent actin signaling pathway.

198 Mechanisms by which NPM-ALK signaling regulates cell migration, invasion and con

199 BB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients.

200 trategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell li

201 fails to effectively inhibit the activity of ALK when activating mutations are present within its kin

202 ogression-free survival (PFS) in a cohort of ALK-rearranged patients.

203 We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay t

204 Detection of ALK rearrangements is currently achieved in clinics thro

205 The efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma

206 ot survival, whereas long-term expression of ALK(F1174L) elicits cell-cycle exit, differentiation, an

207 for tumor cell survival in diverse forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations.

208 Oncogenic kinase fusions of ALK, ROS1, RET, and NTRK1 act as drivers in human lung a

209 erein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-prolife

210 Together, combined inhibition of ALK and MDM2 may provide an effective treatment for TP53

211 ly deleted Cdc42 or Rac1 in a mouse model of ALK-rearranged ALCL to show that either Cdc42 or Rac1 de

212 cant association between baseline numbers of ALK-rearranged or ALK-CNG CTCs and PFS was observed.

213 its promoter region, and the distal part of ALK, including the coding sequence for the entire kinase

214 In the presence of ALK(F1174L) signaling, MYCN induces the expression of th

215 istinct subsets according to the presence of ALK-rearrangement and/or ALK-CNG signals.

216 ined by mutually exclusive rearrangements of ALK, DUSP22/IRF4, and TP63 Genetic alterations affecting

217 and downstream signal pathway regulation of ALK.

218 t of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivative

219 Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazol

220 potency and altered the protein structure of ALK.

221 conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression o

222 sults show that WASp is a novel substrate of ALK and has a critical role in regulating invasiveness a

223 Residual tumor burden following treatment of ALK or ROS1(+) lung cancer patients with oncogene-target

224 d is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subse

225 ompound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays.

226 ent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the bloo

227 to the presence of ALK-rearrangement and/or ALK-CNG signals.

228 on-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in

229 ublet therapy or 3 or more months of EGFR or ALK inhibitors for patients with EGFR mutations or ALK r

230 al Application: Patients with EGFR-mutant or ALK-positive non-small-cell lung cancer with brain metas

231 omarkers, including EGFR or KRAS mutation or ALK translocation status.

232 hibitors for patients with EGFR mutations or ALK rearrangements, respectively.

233 etween baseline numbers of ALK-rearranged or ALK-CNG CTCs and PFS was observed.

234 ed significant cross-resistance to all other ALK inhibitors.

235 LK mutants resistant to crizotinib and other ALK inhibitors.

236 Within our ALK drug discovery program, we identified compound 1, a

237 nts with advanced malignancies, particularly ALK-rearranged NSCLC.

238 cells (CTC) with aberrant ALK-FISH patterns [ALK-rearrangement, ALK-copy number gain (ALK-CNG)] monit

239 ighly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most

240 nificant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish

241 Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the bloo

242 stoma (BEND5-ALK) and an astrocytoma (PPP1CB-ALK), novel BRAF fusions in an astrocytoma (BCAS1-BRAF)

243 nstrated in cell lines as well as in primary ALK- ALCL tumors.

244 inib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC).

245 errant ALK-FISH patterns [ALK-rearrangement, ALK-copy number gain (ALK-CNG)] monitored on crizotinib

246 The TGF-beta-Type I receptor (ALK-5) antagonist SB431542 and Smad2 siRNA, but neither

247 study, 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or ino

248 ative ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-ba

249 The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB

250 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safe

251 ylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the inve

252 rity of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in

253 he vast majority of children with high-stage ALK+ ALCL.

254 The SQ HDM SLIT-tablet (ALK) has been developed for treatment of house dust mite

255 utations (F1174L and D1091N) by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induce

256 GTPases Cdc42 and Rac1 are activated by the ALK oncogenic activity.

257 tinib developed because of a mutation in the ALK kinase domain.

258 of 5a led to significant differences in the ALK potency and altered the protein structure of ALK.

259 e targeted therapies are used to inhibit the ALK-EML4 fusion protein.

260 Purpose Fusions involving the ALK gene are the predominant genetic lesion underlying p

261 arch for a recently validated isoform of the ALK gene and characterized the potential functional impl

262 We assessed the activity of the ALK inhibitor crizotinib in patients who had no known cu

263 sectable IMT highlight the importance of the ALK pathway in these diseases.

264 e in situ hybridization (FISH) targeting the ALK rearrangement.

265 d integrin activation on neutrophils via the ALK-5/TGF-betaRII heterodimer.

266 A 'drug holiday' where the ALK TKI treatment is suspended could represent a therape

267 an NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosi

268 all-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as

269 rranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFR(T790M)-positive NS

270 , and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracrani

271 n of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK

272 roliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and

273 -positive NSCLC; one patient had unconfirmed ALK and ROS1 status.

274 ing keratoplasty (PK) (adjusted HR, 1.12 vs. ALK and 1.10 vs. EK; P < 0.001), postoperative lens stat

275 014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated.

276 dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one

277 c lymphoma kinase (ALK) gene associated with ALK-positive non-small-cell lung cancer (NSCLC).

278 ate analysis, the dynamic change of CTC with ALK-CNG was the strongest factor associated with PFS (HR

279 e dynamic change in the numbers of CTCs with ALK-CNG may be a predictive biomarker for crizotinib eff

280 of glaucoma are significantly decreased with ALK and EK compared with PK.

281 atment for TP53 wild-type neuroblastoma with ALK aberrations.

282 tion between the decrease in CTC number with ALK-CNG on crizotinib and a longer PFS (likelihood ratio

283 le patients were aged 18 years or older with ALK-rearranged locally advanced or metastatic cancer tha

284 nhibitor therapy might benefit patients with ALK- ALCL who are phosphorylated STAT3<sup/>.

285 efficacy of ALK inhibitors in patients with ALK-mutant neuroblastoma is limited, highlighting the ne

286 ld be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.

287 vity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib.

288 ctive therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currentl

289 y and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib

290 naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer

291 ors and determine outcomes for patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and br

292 with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer.

293 o assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metasta

294 updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recomme

295 All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response

296 or treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as

297 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment

298 reated and ALK inhibitor-naive patients with ALK-rearranged NSCLC.

299 cruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung canc

300 ibitor, was effective in vivo in a xenograft ALK- ALCL model.