lapatinib

Overview

Lapatinib (Tykerb) is an oral small-molecule reversible inhibitor of both EGFR and ERBB2 (HER2) tyrosine kinase domains. It is FDA-approved for HER2-positive metastatic breast cancer in combination with capecitabine and for HER2+ metastatic/locally advanced breast cancer in combination with letrozole. It blocks downstream MAPK and PI3K/AKT signaling from both receptors.

Evidence in the corpus

  • In HER2+ OE19 (esophageal) and HER2+ NCI-N87 (gastric) cancer cell viability assays, lapatinib was used as a dual EGFR/HER2 TKI comparator; T-DM1 was more potent than lapatinib at sub-nanomolar concentrations in HER2+ cells, demonstrating that cytotoxic payload delivery via ADC surpasses receptor signal inhibition in this context PMID:27698471.
  • Lapatinib represents the ErbB signal-inhibition strategy that the paper argues is suboptimal due to bypass-pathway resistance (downstream signaling via alternate ErbB members, PI3K/RAS pathways), which the ADC approach circumvents PMID:27698471.
  • Included in the CCLE pharmacogenomic screen across 947 cancer cell lines; sensitivity correlated with genomic features via elastic-net regression PMID:22460905
  • NCI-60 CellMiner pharmacogenomics analysis linked EGFR/ERBB2 pathway activity to lapatinib sensitivity across cancer cell lines including colon PMID:22802077
  • EGFR over-expression and phosphorylation in the PI3K/AKT/mTOR alteration module in clear cell renal cell carcinoma (CCRCC) was linked to prior lapatinib response data (Ravaud et al. 2008 phase III trial) in this cancer type PMID:23792563.
  • Candidate therapy for ERBB4-mutated (6.8%) and NRG1-mutated (7.1%) gastric adenocarcinoma (STAD): dual TKI inhibits ERBB4 and PI3K-AKT signaling; NRG1/ERBB4 mutations occur in 11.6% of GC (34/294), defining a candidate biomarker-selected population; in phase III trial NCT01264081 in ERBB4-mutated melanoma at time of publication PMID:25583476

Resistance mechanisms

  • Bypass-pathway activation (via alternate EGFR/ERBB2/ErbB3/ErbB4 signaling) is cited as a general limitation of EGFR/HER2 signal-inhibition strategies including lapatinib, motivating ADC-based approaches PMID:27698471.

Cancer types (linked)

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:25583476

This page was processed by crosslinker on 2026-05-14.