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Updated: Jun 22, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program
Richard Gorlick1, E Anders Kolb, Peter J Houghton
1The Children's Hospital at Montefiore, Bronx, New York 10467, USA.
Background:
Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer.
Methods:
Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 microM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid(-/-) mice.
Results:
The median IC(50) value for lapatinib against the entire PPTP cell line panel was 6.84 microM (range, 2.08 to >10.0 microM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values.
Conclusions:
Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.
Insights
Lapatinib showed limited efficacy in pediatric cancer models, with in vitro activity at high concentrations. This suggests differences in EGFR/ErbB2 targeting applicability between adult and pediatric cancers.
Area of Science:
- Oncology
- Pharmacology
Background:
- Lapatinib is a reversible tyrosine kinase inhibitor targeting EGFR and ErbB2.
- It demonstrates in vitro and in vivo activity against adult cancer cell lines and efficacy in ErbB2-overexpressing breast cancer.
Purpose of the Study:
- To evaluate the efficacy of Lapatinib in pediatric cancer models.
- To assess Lapatinib's activity against a panel of pediatric cancer cell lines and xenografts.
Main Methods:
- Lapatinib was tested in vitro against the PPTP cell line panel (1.0 nM to 10.0 microM).
- In vivo studies involved oral administration to PPTP xenografts (160 mg/kg twice daily for 6 weeks).
- Pharmacokinetic parameters were determined in scid(-/-) mice.
Main Results:
- The median IC50 for Lapatinib was 6.84 microM against the cell line panel.
- Lapatinib was well tolerated in vivo with minimal toxicity (1.5%).
- Limited efficacy was observed in xenografts, with no objective responses in solid tumor or ALL panels.
Conclusions:
- Lapatinib demonstrated limited activity in the studied pediatric xenograft models.
- In vitro activity was observed at concentrations exceeding specific EGFR/ErbB2 inhibition levels.
- Findings suggest potential fundamental differences in EGFR family member therapeutic targeting between adult and pediatric cancers.
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