Drug Information

Drug (ID: DG02164) and It's Reported Resistant Information

• Name: Farnesyltransferase Inhibition
• Synonyms: Farnesyltransferase Inhibition
• Indication:
  In total 1 Indication(s)
  . .; .; [1]

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: GTPase Nras (NRAS) [1]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Loss
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CHLA-15 cells; Brain; Homo sapiens (Human); CVCL_6594
• In Vitro Model: CHLA-20 cells; Brain; Homo sapiens (Human); CVCL_6602
• In Vitro Model: CHLA-90 cells; Brain; Homo sapiens (Human); CVCL_6610
• In Vitro Model: CHLA-95 cells; Brain; Homo sapiens (Human); CVCL_6611
• In Vitro Model: CHLA-171 cells; Brain; Homo sapiens (Human); CVCL_6597
• In Vitro Model: COG-N-426 cells; Brain; Homo sapiens (Human); CVCL_LF58
• In Vitro Model: COG-N-415 cells; Brain; Homo sapiens (Human); CVCL_AQ23
• In Vitro Model: COG-N-557 cells; Brain; Homo sapiens (Human); CVCL_0389
• In Vitro Model: LA-N-5 cells; Brain; Homo sapiens (Human); CVCL_0389
• In Vitro Model: LA-N-6 cells; Bone marrow; Homo sapiens (Human); CVCL_1363
• In Vitro Model: NB-1643 cells; Adrenal; Homo sapiens (Human); CVCL_5627
• In Vitro Model: NB-EBC1 cells; Brain; Homo sapiens (Human); CVCL_E218
• In Vitro Model: SK-N-FI cells; Brain; Homo sapiens (Human); CVCL_1702
• In Vitro Model: SMS-LHN cells; Brain; Homo sapiens (Human); CVCL_9539
• In Vitro Model: CHP-134 cells; Adrenal gland; Homo sapiens (Human); CVCL_1124
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: LA-N-1 cells; Brain; Homo sapiens (Human); CVCL_1827
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: GI-ME-N cells; Brain; Homo sapiens (Human); CVCL_1232
• In Vitro Model: NBL-S cells; Brain; Homo sapiens (Human); CVCL_2136
• In Vitro Model: NGP cells; Lung; Homo sapiens (Human); CVCL_2141
• In Vivo Model: NSG mice model; Mus musculus
• Experiment for Molecule Alteration: PCR; RNA and miRNA extraction assay; RT-qPCR; Gene expression analysis; Immunoblotting assay; Dual-luciferase assay; Immunohistochemistry
• Experiment for Drug Resistance: Cell viability assay; Synergy assay; Cell cycle assay; Apoptosis assay; Magnetic resonance imaging assay
• Mechanism Description: Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

References

• Ref 1: Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma. Nat Commun. 2024 Apr 23;15(1):3422.