RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer
Violeta Serra, … , So Young Kim, José Baselga
Violeta Serra, … , So Young Kim, José Baselga
Published May 1, 2013
Citation Information: J Clin Invest. 2013;123(6):2551-2563. https://doi.org/10.1172/JCI66343.
View: Text | PDF | Corrigendum
Research Article Oncology

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

Abstract

The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.

Authors

Violeta Serra, Pieter J.A. Eichhorn, Celina García-García, Yasir H. Ibrahim, Ludmila Prudkin, Gertrudis Sánchez, Olga Rodríguez, Pilar Antón, Josep-Lluís Parra, Sara Marlow, Maurizio Scaltriti, José Pérez-Garcia, Aleix Prat, Joaquín Arribas, William C. Hahn, So Young Kim, José Baselga

×

Figure 6

In vivo modeling of RSK4 resistance phenotype and the use of ERK pathway inhibitors to overcome resistance.

Options: View larger image (or click on image) Download as PowerPoint
In vivo modeling of RSK4 resistance phenotype and the use of ERK pathway...
(A) Mouse xenograft experiment with MCF7 cells overexpressing RSK4 or GFP control. Mice were treated 6 times per week (6IW) with BEZ235 (30 mg/kg) or vehicle for 24 days (end of experiment). Box plots represent tumor volumes, with whiskers depicting minimum and maximum. A 2-tailed Student’s t test compares the 2 treated populations. *P < 0.05 (mean ± SEM, n = 8). (B) Tumors were harvested at 24 days and analyzed by IHC for phosphorylation of rpS6235/236 and RSK4 expression. Representative images are shown in top panel. H-Score quantification of IHC analysis of rpS6235/236, bottom panel. A 2-tailed Student’s t test compares the 2 treated populations. **P < 0.01 (mean ± SEM). Original magnification, ×40; ×400 (enlarged). (C) Mouse xenograft assay with MCF7 cells overexpressing RSK4 or GFP control. Mice were treated 6 times per week with single agent BEZ235 (25 mg/kg, 6IW) or MEK162 (6 mg/kg, twice daily, BID) or in combination. Boxes represent tumor volume variation; lines represent mean tumor volume; bars represent SEM. A 2-tailed Student’s t test compares the treated versus untreated tumors. **P < 0.01 (mean ± SEM, n = 8). (D) Tumors generated in C were analyzed by IHC for phosphorylation of rpS6236/236. Representative images are displayed. Original magnification, ×400. (E) H-Score quantification of IHC analysis of rpS6235/236 of tumors from Figure 5C, A 2-tailed Student’s t test compares the 2 treated populations. **P < 0.01 (mean ± SEM).