Molecule Information

General Information of the Molecule (ID: Mol04272)

• Name: Pan-HER family receptors (Pan-HERs) ,Homo sapiens
• Synonyms: Pan-HER family receptors (Pan-HERs)
• Molecule Type: Protein

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Lapatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Head and neck cancer [ICD-11: 2D42.0] [1]

• Sensitive Disease: Head and neck cancer [ICD-11: 2D42.0]
• Sensitive Drug: Lapatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: 4NQO-L cells; Tongue; Homo sapiens (Human); N.A.
• In Vitro Model: 4NQO-T cells; Tongue; Homo sapiens (Human); N.A.
• In Vivo Model: C57BL/6 J male mice model; Mus musculus
• Experiment for Molecule Alteration: Western blot assay; Immunohistochemistry; Immunofluorescence staining assay
• Experiment for Drug Resistance: IC50 assay; Cell proliferation assay; CD8+ depletion assay
• Mechanism Description: Results: Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of alphaPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with alphaPD-1 did not improve the outcome.

References

• Ref 1: Dual inhibition of HERs and PD-1 counteract resistance in KRAS(G12C)-mutant head and neck cancer. J Exp Clin Cancer Res. 2024 Nov 20;43(1):308.