Amplification of the HER2 oncogene happens in around 25% of human breast cancers and confers a poor prognosis but also renders tumors susceptible to HER2 targeted therapies. Lapatinib, a compact molecule, ATP competitive tyrosine kinase inhibitor of HER2, is surely an useful therapy for sufferers with HER2 overexpressing metastatic breast cancer. Nevertheless, most sufferers treated with lapatinib sooner or later relapse following treatment, suggesting that tumors acquire or intrinsically possess mechanisms for escape from HER2 inhibition. In HER2 overexpressing cells, the main mechanism of PI3K activation is heterodimerization with kinase deficient HER3, which when phosphorylated couples for the p85 regulatory subunit of PI3K.
Treatment method of HER2 overexpressing cells with lapatinib blocks HER3 phosphorylation and uncouples p85 from HER3, therefore inhibiting PI3K Akt. Sustained inhibition of HER2 HER3 output to PI3K Akt has R547 clinical trial been proposed for being critical for that antitumor result of HER2 inhibitors. Recently, inhibition of HER2 phosphorylation from the EGFR TKI gefitinib in HER2 overexpressing human breast cancer cells was proven to get followed by suggestions upregulation of activated HER3 and Akt, thus limiting the inhibitory effect of gefitinib. Therapeutic doses of lapatinib can also be followed by suggestions upregulation of phosphorylated HER3 in HER2 dependent breast cancer cells that’s only abrogated by pulsed supra pharmacological doses. Additionally, aberrant activation of the PI3K pathway has become connected with resistance towards the HER2 inhibitors trastuzumab and lapatinib.
Src loved ones kinases are intracellular tyrosine kinases implicated in signal transduction downstream of a number of signaling networks like the ErbB receptors. Src association with HER2 is shown in human breast cancer cell lines and primary tumors. The interaction is certain for that HER2 kinase domain and results in enhanced Src kinase activity and protein stability. Interestingly, reversible Aurora Kinase inhibitor inhibition of a Src mediated inhibitory phosphorylation of PTEN continues to be recommended as component within the antitumor mechanism of trastuzumab. Because of its involvement in multiple signaling cascades, Src is now an desirable therapeutic target with numerous Src inhibitors in clinical growth. We produced lapatinib resistant derivatives of HER2 overexpressing human breast cancer cell lines. Each one of these lines exhibit HER2 amplification and sensitivity to lapatinib with submicromolar IC50s. Lapatinib resistant cells exhibited recovery of PI3K Akt signaling in spite of continued inhibition within the HER2 tyrosine kinase. Making use of a mass spectrometry primarily based phosphoproteomic method in BT474 cells, we found upregulation of Src loved ones kinase activity during the resistant cells.