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. 2018 May 24;9(6):621. doi: 10.1038/s41419-018-0691-x

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a, b Lapatinib-resistant human BT474R cells exhibit a two-fold increased viability after 48 h treatment with lapatinib (a) and a significantly decreased apoptosis after treatment with 300 nM lapatinib for indicated times (measured by cleaved PARP, b) compared to lapatinib-sensitive parental BT474 cells. b Western blot analysis, GAPDH is a loading control. One representative experiment out of two independent experiments (each performed in triplicate) is shown; **p < 0.01 for three technical replicas, Student’s t-test (a). c Tumor onset is significantly delayed in R172H/+;ERBB2 females treated with 75 mg/kg lapatinib three times a week starting at 8 weeks of age lifelong (red line) compared to vehicle-treated siblings (black line). Kaplan–Meier analysis, log rank statistics. d, e Murine primary cell lines established from lapatinib-sensitive mammary tumors (1252, 1253, 1349) and from a lapatinib-resistant mammary tumor (125R) maintain lapatinib sensitivity and lapatinib resistance in vitro, respectively. d Short-term cell viability assay (48 h). One representative experiment out of two independent experiments (each performed in triplicate) is shown; **p < 0.01 for three technical replicas, Student’s t-test. e Long-term colony formation assay (4 weeks). f Lapatinib induces activation of multiple adaptive RTKs in vivo. Representative images of the mouse Phospho-RTK array kit comparing lapatinib-treated (i.e., lapatinib-resistant, top) with vehicle-treated (i.e., lapatinib-sensitive, bottom) tumors. 1. EGFR*, 2. ERBB2*, 3. ERBB3, 4. PDGFRα*, 5. PDGFRβ*, 6. Axl*, 7. NGFR, 8. VEGFR1*, 9. MUSK*, 10. EPHA2*, 11. EPHB2. Known Hsp90 clients are marked with an asterisk. Triangles mark reference spots. g, h Murine lapatinib-resistant 125R cells show upregulated PDGFRα and PDGFRβ compared to murine lapatinib-sensitive cells 1349, 1251, 1252, 1253 (g), while human lapatinib-resistant BT474R cells have upregulated MET and downregulated ErbB2 and EGFR signaling (measured by phospho-ERBB2 pY1221/2 and pY1248, two top panels, phospho-EGFR and their effector phospho-Erk), compared to parental BT474 cells (h). Note that both human and mouse lapatinib-resistant cells have upregulated HSF1 and its transcriptional targets Hsp90 (g) and Hsp70 (h). Western blot analysis, constitutive heat shock protein 70 (Hsc70) and GAPDH served as a loading control