Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2007 Aug;40(4):580-94.
doi: 10.1111/j.1365-2184.2007.00455.x.

Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines

D W Rusnak  1 , K J Alligood, R J Mullin, G M Spehar, C Arenas-Elliott, A-M Martin, Y Degenhardt, S K Rudolph, T F Haws Jr, B L Hudson-Curtis, T M Gilmer
Affiliations

Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines

D W Rusnak et al. Cell Prolif. 2007 Aug.

Abstract

Objective: Lapatinib (Tykerb, GW572016), a potent inhibitor of the catalytic activities of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (ErbB2), inhibits population growth of selected EGFR and HER2 overexpressing cell lines. Previous studies with a small number of cell lines suggest a correlation between overexpression of EGFR and/or HER2 and sensitivity to growth inhibition by lapatinib; however, the precise determinants of lapatinib selectivity for tumour and/or other cells remain unclear.

Materials and methods: To clarify the determinants of its selectivity in cultured cells, lapatinib-induced cell population growth inhibition and relative EGFR and HER2 protein expression were quantified in 61 different human tumour cell lines from 12 tumour types, two oncogene transformed human cell lines and two normal human cell cultures. Using statistical tools to analyse the data, a model describing the relationship between lapatinib IC(50) (the response variable) and EGFR and HER2 expression and tissue type (explanatory variables) was derived.

Conclusion: The results suggest that simultaneous consideration of EGFR and HER2 expression, as well as tissue type yields the best determinant of lapatinib selectivity in cultured cells.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Scatter plots showing the relationship between individual receptor expression and cellular pIC50. (a) EGFR expression and cellular IC50. A number of cell lines with high levels of HER2 (open diamonds) are responsive to lapatinib, despite modest levels of EGFR expression. (b) HER2 expression and cellular IC50. Two of the three cell lines with high levels of EGFR expression (open diamonds) are responsive to lapatinib, despite modest levels of HER2 expression.
Figure 2
Figure 2
Fitted surfaces showing the effect of EGFR and HER2 expression on response to lapatinib. The natural log of EGFR and HER2 expression is plotted against the IC50 for lapatinib in a three‐day cellular proliferation assay. One cell line had an EGFR expression level and one cell line had an HER2 expression level below the limit of detection which was defined as zero. For this reason, a value of 0.25 was added to the expression level of EGFR and HER2 for all cell lines. Left panel: As EGFR expression increases, there is a commensurate drop in cellular IC50. As HER2 expression increases, there is quadratic relationship between the natural logarithm of expression and efficacy. Tissue of origin for each cell line was also used to generate the fitted surface. Right panel: the same surface rotated to more readily visualize the predicted IC50 at higher levels of HER2.
Figure 3
Figure 3
Residual plot shows the difference between predicted and actual cellular IC50 values for 65 cell lines as the ratio of actual/predicted on the log base 10 scale.
Figure 4
Figure 4
Plot of the natural log of predicted versus actual IC50 values on the log base 10 scale. Each symbol on the graph represents a single cell line. Color symbols indicate tumor tissue of origin.
Figure 5
Figure 5
HNSCC tumor cell lines, plot of the natural log of predicted versus actual IC50 value on the log base 10 scale. Multivariate assessment of the effect of HPV risk and EGFR/HER2 expression on lapatinib sensitivity (a) is a better predictor of lapatinib sensitivity than assessment of only EGFR and HER2 expression (b).
See this image and copyright information in PMC

References

    1. Burris HA, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J. Clin. Oncol. 23, 5305–5313. - PubMed
    1. Cohen MH, Johnson JR, Chen YF, Sridhara R, Pazdur R (2005) FDA drug approval summary: erlotinib (Tarceva®) tablets. Oncologist 10, 461–466. - PubMed
    1. Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn Jr WD, Morse D, Abraham S, Rahman A, Liang C, Lostritto R, Baird A, Pazdur R (2004) United States Food and Drug Administration Drug Approval Summary Gefitinib (ZD1839; Iressa) Tablets. Clin. Cancer Res. 10, 1212–1218. - PubMed
    1. Fabian MA, Biggs III WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ (2005) A small molecule–kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23, 329–336. - PubMed
    1. Fakhry C, Gillison M (2006) Clinical implications of human papillomavirus in head and neck cancers. J. Clin. Onc. 24, 2606–2611. - PMC - PubMed