AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity

By S. Chandarlapaty, A. Sawai, M. Scaltriti, V. Rodrik-Outmezguine, O. Grbovic-Huezo, V. Serra, P. Majumder, J. Baselga, N. Rosen. Cancer Cell, 2011

975 citations recorded by the source corpus.

Summary Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs including HER3, IGF-1R, and Insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/ff6c553357e104b36d1d03de46ccbb60b626726e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

In Pathology and Forensic Medicine

Citations in the corpus

ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics (2014, background): “Analogous to the effects of inhibition of the MEK pathway, inhibition of the PI3K pathway leads to potent activation of HER3-dependent signaling in HER2-amplified breast cancers (Chakrabarty et al., 2012; Chandarlapaty et al., 2011).”
The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches (2012, background): “Interestingly, combinations of inhibitors of RTKs and PI3K signalling inhibitors were able to prevent the activation of compensatory mechanisms leading to increased expression and activation of RTKs following treatment with PI3K inhibitors [6,7].”
The insulin and insulin-like growth factor receptor family in neoplasia: an update (2012, background): “Thus, blockade of PI3K signalling is anticipated not only to cause compensatory changes at the cellular level, which may limit therapeutic efficac”
An Integrated Mechanistic Model of Pan-Cancer Driver Pathways Predicts Stochastic Proliferation and Death (2017, background): “Such predictions would have engrained within important properties of clinical response such as the promiscuity of many targeted kinase inhibitors (Davis et al., 2011) and dynamic feedback mechanisms in cancer cells important for resistance (Chandarlapaty et al., 2011).”
Dynamic Reprogramming of the Kinome In Response to Targeted MEK Inhibition In Triple Negative Breast Cancer (2012, positive): “In addition to c-Myc, inhibition of AKT and mTOR also causes kinome reprogramming in different breast cancer subtypes (Chandarlapaty et al., 2011; Rodrik-Outmezguine et al., 2011).”
The PI3K pathway in human disease (2017, positive): “One frequent mechanism involves increased transcription of genes encoding RTKs, most notably HER3, EGFR, and INSR/IGFR1 (Chakrabarty et al., 2012; Chandarlapaty et al., 2011; Muranen et al., 2012).”