Fig. 3: MAPK pathway activating mutants promote MEK dependence.
From: HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway
(a) Inhibition of proliferation of SKBR3 shRenilla and shNF1 HER2i-R cells by lapatinib (HER2i), MK2206 (AKTi), trametinib (MEKi), and SCH772984 (ERKi), plotted as % inhibition of proliferation after 5 days treatment vs log concentration of drug (nM). Data represent means of 6 biological replicates. (b) Crystal violet staining of shRenilla and shNF1 HER2i-R SKBR3 cells exposed to indicated doses of trametinib (MEKi) over 7 days. Data are representative images of 3 biological replicates. (c) Inhibition of proliferation of shRen and HER2 inhibitor resistant (HER2i-R) shNF1, HER2 L755S-expressing, and KRAS G12V-expressing SKBR3 cells by trametinib (MEKi). (d) Growth of BT-474 shRenilla and shNF1 HER2i-R xenograft tumors treated with vehicle or 1 mg/kg trametinib daily. n = 10 mice per group, data are means ± SEM. P value = 0.0059 by two-sided student’s t-test. (e) Immunohistochemistry staining of phosphor-ERK1/2 in BT-474 xenograft tumor sections from (d). Images are representative of 4 tumors per treatment group. Scale bars = 100 um (f) Growth of patient-derived xenograft harboring ERBB2 amplification and NF1 deletion in mice treated with vehicle, 10 mg/kg trastuzumab bi-weekly, 1 mg/kg trametinib weekly, or the combination. N = 5 mice per group bearing two tumors each, data are means ± SEM. P value < 0.00103 by two-sided student’s t-test. (g) Immunohistochemistry staining of phospho-ERK in NF1 null PDX tumors from (f), scale bar 100 um. Source data for all assays are provided as a Source Data file.
