Drug Information

Drug (ID: DG02161) and It's Reported Resistant Information

• Name: Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors
• Synonyms: Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors
• Indication:
  In total 1 Indication(s)
  . .; .; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [1]

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatidylinositol 3-kinase (PI3K) [1]

• Resistant Disease: B-cell non-Hodgkin lymphoma [ICD-11: 2A85.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Phosphatidylinositol 3-kinase gamma; Regulation; N.A.
• In Vitro Model: TS cells; Head and Neck; Homo sapiens (Human); CVCL_VH06
• In Vitro Model: SU-DHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0538
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: JB6 [Human anaplastic large cell lymphoma] cells; Lymphoid; Homo sapiens (Human); CVCL_H633
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vitro Model: DEL cells; Pleural effusion; Homo sapiens (Human); CVCL_1170
• In Vitro Model: L-82 cells; Pleural effusion; Homo sapiens (Human); CVCL_2098
• In Vitro Model: Mac-1 cells; Lymph; Homo sapiens (Human); CVCL_H631
• In Vitro Model: FE-PD cells; Lymph; Homo sapiens (Human); CVCL_H614
• In Vitro Model: CEM cells; Lymph; Homo sapiens (Human); N.A.
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: Murine cells; Lymph; Homo sapiens (Human); N.A.
• In Vivo Model: CD4-NPM-ALK xenograft mice model; PI3KgammaCX/CX xenograft mice model; PI3Kgamma-/- xenograft mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; Fluorescence in situ hybridization assay; Histology assay; Immunohistochemistry; qRT-PCR; Flow cytometry
• Experiment for Drug Resistance: Cell proliferation assay; Apoptosis assay; Cell viability assay; Drug sensitivity assay; Chemokine assay
• Mechanism Description: Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase gamma (PI3K-gamma) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kgamma expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kgamma, and PI3Kdelta were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kgamma isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kgamma/delta inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kgamma or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

References

• Ref 1: Targeting CCR7-PI3Kgamma overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma. Sci Transl Med. 2023 Jun 28;15(702):eabo3826.