Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies

TLDR

Targeted RTK and PI3K inhibitors show limited efficacy in glioblastoma and other solid tumors. The study hypothesizes that coactivation of multiple RTKs sustains downstream signaling and limits the effectiveness of single‑RTK therapies. Tumor cells exhibit coactivated RTKs, and only combined RTK inhibition reduces signaling, survival, and growth, indicating that multi‑RTK targeting is required for effective GBM therapy.

Abstract

Targeted therapies that inhibit receptor tyrosine kinases (RTKs) and the downstream phosphatidylinositol 3-kinase (PI3K) signaling pathway have shown promising anticancer activity, but their efficacy in the brain tumor glioblastoma multiforme (GBM) and other solid tumors has been modest. We hypothesized that multiple RTKs are coactivated in these tumors and that redundant inputs drive and maintain downstream signaling, thereby limiting the efficacy of therapies targeting single RTKs. Tumor cell lines, xenotransplants, and primary tumors indeed show multiple concomitantly activated RTKs. Combinations of RTK inhibitors and/or RNA interference, but not single agents, decreased signaling, cell survival, and anchorage-independent growth even in glioma cells deficient in PTEN, a frequently inactivated inhibitor of PI3K. Thus, effective GBM therapy may require combined regimens targeting multiple RTKs.