Disease Information

General Information of the Disease (ID: DIS00569)

• Name: Unspecified malignant neoplasms of unspecified sites
• ICD: ICD-11: 2D4Z

Type(s) of Resistant Mechanism of This Disease

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Selpercatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor tyrosine-protein kinase erbB-3 (ERBB3) [1]

• Resistant Disease: ret-aberrant cancers [ICD-11: 2D4Z]
• Resistant Drug: Selpercatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: YAP-HER3 signaling pathway; Regulation; N.A.
• In Vitro Model: LC2/ad cells; Pleural effusion; Homo sapiens (Human); CVCL_1373
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: TT cells; Thyroid gland; Homo sapiens (Human); CVCL_1774
• In Vivo Model: Severe combined immunodeficiency mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; RT-PCR; RNA sequencing assay; Phospho-receptor tyrosine kinase antibody arrays assay; Chromatin immunoprecipitation assay; Luciferase reporter assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.

References

• Ref 1: YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers. Clin Cancer Res. 2025 Mar 17;31(6):1127-1141.