The HSP-RTK-Akt axis mediates acquired resistance to Ganetespib in HER2-positive breast cancer

摘要

a Tumor volume over time in Lapatinib-resistant ErbB2 mice. After acquiring Lapatinib resistance, mice were treated with Vehicles, Lapatinib alone (which was no longer effective), or Lapatinib and Ganetespib together. Tumor size was normalized to the respective initial size (when treatments started), which was on average 2,501 ± 156 mm3. Mean ± SEM, *p < 0.05, **p < 0.01 (top asterisks, vs. Vehicles; bottom asterisks, vs. Lapatinib alone), unpaired two-tailed Student’s t-test. b Overall survival of Neu (left) and ErbB2 (right) mice with or without (Control) Ganetespib injections, weeks after the onset of the autochthonous mammary tumors (when treatments started). Note that Ganetespib approximately doubles the overall survival in both models. Kaplan–Meier analysis, p, Log Rank statistics. Shaded areas are 95% confidence interval. c, d The dynamics of tumor growth over time in Neu (c) and ErbB2 (d) mice with or without (Control) Ganetespib injections performed as in b. Note that after the initial period of regression/stagnation for about 4 weeks, tumors in both models regrow due to acquired resistance. Tumor size was normalized to their respective initial size (when treatments started), which was 233 ± 22 mm3 and 251 ± 23 mm3 (c); 157 ± 45 mm3 and 146 ± 40 mm3 (d) for Control and Ganetespib groups, respectively. c, d, left growth of individual tumors, c, d, right average tumor growth. Mean ± SEM, *p < 0.05, **p < 0.01, unpaired two-tailed Student’s t-test.