ライフサイエンスコーパス: ALK

1 ALK inhibitors could be useful in enhancing D2R signalin

2 ALK phosphorylation increased by almost 2-fold after dop

3 ALK was also transactivated by and associated with dopam

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

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

6 ALK+ lymphomas were accelerated in WASP- and WIP-deficie

7 ALK, ROS1 and RET gene fusions are important predictive

8 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0 [IQR, 3.5-13.0]; P < .001

9 BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence.

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

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

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

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 Abrogating ALK activity with kinase inhibitors is employed as clini

17 es and xenograft models expressing activated ALK.

18 e also examined if D2R stimulation activated ALK signaling.

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

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

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

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

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

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

25 omatic hydrocarbons (PAH), PHC, and alkanes (ALK) were very good, good and fair, and in contrast, the

26 All ALK inhibitor resistant cell lines displayed significant

27 l. demonstrate that resistant MYCN-amplified ALK-mutated neuroblastoma cells overexpress BORIS, resul

28 Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1

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

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

31 Dopamine activated protein kinase C in an ALK-dependent manner and a PKC inhibitor blocked dopamin

32 inase Cgamma was activated by dopamine in an ALK-dependent manner, and a protein kinase C inhibitor c

33 ry cutaneous ALCL and systemic type ALK+ and ALK- ALCL.

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

35 Several generations of EGFR and ALK inhibitors have shown activity on brain metastases f

36 n activity on brain metastases from EGFR and ALK mutant non-small-cell lung cancer.

37 e elevated lactate dehydrogenase or EGFR and ALK wild-type populations.

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

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

40 with driver events involving KRAS, EGFR, and ALK.

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

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

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

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

45 ecurrent FGFR1 variants in six patients, and ALK N-terminal structural alterations in five samples, i

46 tions in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhib

47 ctivated protein kinase (MAPK) signaling and ALK pathways, whereas discordant pathways included advan

48 y almost 2-fold after dopamine treatment and ALK coimmunoprecipitated with D2R.

49 tention-to-treat wild-type (ie, EGFR(wt) and ALK(wt)) population.

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

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

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

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

54 study the efficacy of repotrectinib to block ALK activation/signaling.

55 -inducible factor 1alpha), blocking the BMP4/ALK (activin-like kinase) 2/ALK1/ALK5 and Notch signalin

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

57 ological inhibitors of proteins activated by ALK signaling.

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

59 LCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT

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

61 volution of resistance to different clinical ALK inhibitors.

62 Combining ALK inhibition with other novel therapeutic modalities s

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

64 lines indistinguishable from patient-derived ALK+ ALCL.

65 tions with variable sensitivity to different ALK inhibitors.

66 PC12 cells transfected with different ALK mutant variants were used to study the efficacy of r

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

68 ign this series toward compounds with a dual ALK-BRD4 profile.

69 , and 871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK

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

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

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

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

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

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

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

77 tations in EGFR, KRAS, MET, PIK3CA, and EML4-ALK fusion were mostly component-shared.

78 4% of known fusion oncogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET.

79 EML4-ALK fusion RNA without forming the EML4-ALK fusion gene.

80 FISH, we detected a cancer sample with EML4-ALK fusion RNA without forming the EML4-ALK fusion gene.

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

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

83 esses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances (e.g., ABL2, AXL, CSK) invadopodi

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

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

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

87 the PAH and PHC were only fair, and poor for ALK.

88 tion, IHC with or without RNA sequencing for ALK/ROS1/NTRKs/RET fusions, next-generation sequencing f

89 ith crizotinib as a first-line treatment for ALK-positive non-small-cell lung cancer with 600 mg of a

90 twice per day as a first-line treatment for ALK-positive non-small-cell lung cancer.

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

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

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

94 ase I clinical trial of the first generation ALK inhibitor, crizotinib, in neuroblastoma patients sho

95 Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range o

96 in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further s

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

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

99 derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceri

100 t from activated oncogenic variants of human ALK, suggesting that our screen identified targets likel

101 sly, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipopr

102 genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resista

103 Taken together, these results identify ALK as a receptor tyrosine kinase transactivated by D2R

104 done before lorlatinib treatment to identify ALK resistance mutations.

105 idin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, w

106 In ALK(+) ALCLs, squalene alters the cellular lipid profile

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

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

109 me the mechanism of cancer drug addiction in ALK-positive ALCL and the benefit of scheduled intermitt

110 achieve a more potent therapeutic effect in ALK+ ALCL.

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

112 ess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (N

113 of BORIS promotes chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma(10) cells that

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

115 roactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome

116 y against most known resistance mutations in ALK and ROS1.

117 0 months (95% CI 11.3-non-estimable [NE]) in ALK inhibitor-naive patients and 8.3 months (6.8-9.7) in

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

119 e of cholesterol auxotrophy, particularly in ALK(+) anaplastic large cell lymphoma (ALCL) cell lines

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

121 scribe a mechanism of TGF-beta resistance in ALK-positive tumours, including lymphoma, lung cancer an

122 oncogenic ALK restores TGF-beta responses in ALK-positive tumour cells.

123 We demonstrate that, in ALK-positive tumours, ALK directly phosphorylates SMAD4

124 provides guidance for targeted therapies in ALK-positive cancers.

125 ic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reporte

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

127 as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2,

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

129 For instance, ALK-rearranged renal cell carcinomas have shown response

130 STAT3 acetylation relied on intact ALK-induced PI3K- and mTORC1-dependent signaling and was

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

132 8 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were o

133 is regulated by the receptor tyrosine kinase ALK.

134 vated by BMP9, activin receptor-like kinase (ALK) 1 induces HOXD3 expression.

135 ype I receptor activin receptor-like kinase (ALK)3-dependent phosphorylation (P) of mothers against d

136 nt inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic

137 We discovered anaplastic lymphoma kinase (ALK) as a candidate thinness gene.

138 tyrosine kinase anaplastic lymphoma kinase (ALK) blocked D2R desensitization in neurons in the ventr

139 which fuses the Anaplastic Lymphoma Kinase (ALK) gene with the Nucleophosmin (NPM) gene.

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

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

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

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

147 tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during

148 arison, CNAs for anaplastic lymphoma kinase (ALK)- nodal anaplastic large cell lymphomas (ALCLs; n =

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

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

151 Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lun

152 ene encoding for anaplastic lymphoma kinase (ALK).

153 ceptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded).

154 alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET.

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

156 on arises also in the hematologic malignancy ALK-positive anaplastic large-cell lymphoma (ALCL) resis

157 Interestingly, BMP-9-mediated ALK-1 internalization strongly re-duces LDL transcytosis

158 ng of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization.

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

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

161 t mutations in neuroblastoma, including most ALK and Ras-activating variants.

162 t response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E

163 wnstream of neuroblastoma driver genes MYCN, ALK and PHOX2B.

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

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

166 n-squamous non-small-cell lung cancer and no ALK or EGFR mutations.

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

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

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

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

171 atopoietic precursor differentiation and NPM-ALK+ cell growth.

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

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

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

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

176 We also compared NPM-ALK/ beta-actin ratios determined by ELISA to those inde

177 er cell; based on our in-house developed NPM-ALK ELISA; LOD of 40 pM) as compared to the ubiquitous b

178 . coli, purified and characterized human NPM-ALK fusion protein to be used as a standard for estimati

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

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

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

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

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

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

185 on, leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase.

186 Implantation of NPM-ALK-transformed CD4+ T lymphocytes into immunodeficient

187 and survival were strictly dependent on NPM-ALK activity and include activation of the key factors S

188 min-anaplastic lymphoma kinase-positive (NPM-ALK(+)) anaplastic large-cell lymphoma (ALCL) as model s

189 ansformed CD4+ T lymphocytes and primary NPM-ALK+ ALCL biopsies share similarities with early T cell

190 the first time our findings suggest that NPM-ALK could restore progenitor-like features in mature CD3

191 We estimated that NPM-ALK fusion protein is expressed at substantial levels in

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

193 Integration of "Omic" data revealed that NPM-ALK-transformed CD4+ T lymphocytes and primary NPM-ALK+

194 The NPM-ALK fusion protein is a constitutively-active tyrosine k

195 nancies that are not associated with the NPM-ALK fusion.

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

197 Of note, these NPM-ALK+ lymphoma cells overexpress stem cell regulators (OC

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

199 of normal human CD4+ T lymphocytes with NPM-ALK results in their immortalization and malignant trans

200 the overexpression of the fusion kinase NPM1-ALK, but the mechanism by which ALK overactivity drives

201 Moreover, a novel NPM1-ALK-positive ALCL PDX model showed a significant surviva

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

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

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

205 h targets the active kinase conformations of ALK, ROS1 and TRK receptors.

206 Continuous development of ALK inhibitors has resulted in the third generation inhi

207 dentify the signaling pathways downstream of ALK that might regulate D2R internalization, we used pha

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

209 BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dyna

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

211 euroblastomas, which have a 14% frequency of ALK aberrations at the time of diagnosis and show increa

212 se tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF(1,2).

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

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

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

216 gests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of A

217 h repotrectinib to investigate inhibition of ALK and to determine its effect on proliferation.

218 -1 reduces BMP-9-mediated internalization of ALK-1, BMP-9-dependent signaling and gene expression.

219 -9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and L

220 STAT1 overactivation is the key mechanism of ALK-TKI addiction in ALCL.

221 Here we reveal the mechanism of ALK-TKI addiction in ALCL.

222 Using an experimental model of ALK positive NSCLC, we explored the evolution of resista

223 igh-risk neuroblastoma patients, mutation of ALK and amplification of MYCN.

224 of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leuk

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

226 In patients with overexpression of ALK protein, the response rate was significantly better

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

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

229 inhibiting signaling activity of a range of ALK mutant variants found in neuroblastoma patients and

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

231 is constitutively acetylated as a result of ALK activity.

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

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

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

235 M1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

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

237 cal or genetic interference of the oncogenic ALK restores TGF-beta responses in ALK-positive tumour c

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

239 cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.

240 cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Eval

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

242 ancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncolo

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

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

245 tions in epidermal growth factor receptor or ALK.

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

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

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

249 In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK

250 Anaplastic lymphoma kinase-positive (ALK-positive) disease occurs in approximately 5% of all

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

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

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

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

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

256 ated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastase

257 a broad range of known crizotinib-resistant ALK mutations and CNS metastases.

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

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

260 tree sublingual immunotherapy (SLIT)-tablet (ALK-Abello, Horsholm, Denmark) is developed for treatmen

261 tyrosine kinase inhibitor (TKI) that targets ALK and ROS1 with preclinical activity against most know

262 Mechanistically, we found that ALK expression in hypothalamic neurons controls energy e

263 These results indicate that ALK regulates dopamine D2 receptor trafficking, which ha

264 The ALK inhibitor alectinib completely inhibited dopamine-in

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

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

267 boring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows

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

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

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

271 Mechanisms of acquired resistance to ALK inhibition therapy in neuroblastoma have not yet bee

272 lastoma(10) cells that develop resistance to ALK inhibition.

273 stic large-cell lymphoma (ALCL) resistant to ALK-specific tyrosine kinase inhibitors (TKIs).

274 PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-l

275 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of hig

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

277 e demonstrate that, in ALK-positive tumours, ALK directly phosphorylates SMAD4 at Tyr 95.

278 as primary cutaneous ALCL and systemic type ALK+ and ALK- ALCL.

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

280 a cell-based system, we investigated whether ALK regulates D2R internalization.

281 kinase NPM1-ALK, but the mechanism by which ALK overactivity drives toxicity upon TKI withdrawal rem

282 ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK, and 42 [1.0%] with ROS1 alterations).

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

284 kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic e

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

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

287 ate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase

288 nd how it influences their interactions with ALK-1.

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

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

291 Asian patients, aged 18 years or older, with ALK-positive non-small-cell lung cancer were randomly as

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

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

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

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

296 score of >=50%) and 40% among patients with ALK-positive tumors.

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

298 e-duces LDL transcytosis to levels seen with ALK-1 deficiency.

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.