Abstract P4-01-05: Lapatinib Resistance Confers Cross-Resistance to Microtubule Inhibitors in ErbB2-Overexpressing Breast Cancer Cells

ErbB2 gene amplification occurs in approximately 20% of all breast cancers and is associated with an aggressive subtype with poor clinical prognosis. Acquired resistance to erbB2-targeted therapies is a common occurance even in patients who show an initial clinical response to trastuzumab or lapatinib-based regimens. Optimal treatment for relapsed disease following erbB2 targeted therapies has not been defined. Therefore, we sought to evaluate whether cytotoxic agents have cross-resistance to lapatinib in cell lines that have acquired resistance to lapatinib. Here we established a model of acquired lapatinib resistance derived from erbB2 overexpressing breast cancer cell lines, BT474 and SKBR3. Lapatinib resistant cell lines, BTLapR and SKLapR, were generated by growth in the continuous presence of 2.6 uM lapatinib (peak plasma concentration in human subjects) resulting in IC50 of 4.72 uM (BTLapR) and 0.083 uM (BT474) (P IC 50 of Significant Drugs on Lapatinib Resistant BT474 cells Previous studies have shown that resistance to lapatinib can switch cell survival signaling from the erbB2 to ER pathway, and that ER signaling can stimulate beta III tubulin expression. We therefore hypothesize the differential responses to microtubule inhibitors in BTLapR and SKLapR might be explained by the fact that BT474 has both estrogen (ER) and progesterone receptor (PR), but SKBR3 express neither. Moreover, beta-III tubulin is known to be a key resistance mechanism of microtubule inhibition. Western blot analysis of baseline protein expression in both acquired lapatinib-resistant and parental cells indicates that ER signaling is involved in stimulating beta III tubulin and is linked to the development of resistance to microtubule inhibitors. These findings point to a potential mechanism to address cross resistance between lapatinib and microtubule-interacting agents, which could have potential clinical implications when considering salvage therapies following lapatinib treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-01-05.