Prospects for personalized medicine with inhibitors targeting the RAS and PI3K pathways

Abstract

Tumor genetic analyses have revealed that the signaling pathways regulated by PI3K and RAS are of fundamental importance in a wide variety of human neoplasms, leading to intensive efforts to develop therapeutics that block signaling through these two key pathways. Both pathways frequently undergo a variety of activating alterations, including oncogenic mutations, amplification events and loss of tumor-suppressor genes that are thought to confer aggressive growth properties and enhance survival on neoplastic cells. An attractive hypothesis is that these alterations provide an indication that a particular tumor is addicted to signaling through the affected pathway, thus may provide ideal candidate predictive biomarkers to target these inhibitors to appropriate patient populations. This review highlights recent preclinical progress made on understanding the predictive value of key pathway alterations in response to targeted therapeutics directed against PI3K, AKT, mTOR, BRAF and MEK, and the prospects for biomarker-driven clinical strategies for such inhibitors.

Keywords::

• AKT
• biomarker
• BRAF
• companion diagnostics
• MEK
• mTOR
• personalized medicine
• PI3K
• RAS

Acknowledgements

The author would like to thank Elaine Storm, Carol O’Brien, Zach Boyd and Jill Spoerke for comments on the manuscript and Lukas Amler and Garret Hampton for helpful discussions. This paper is dedicated to the memory of John Charles Sisson, a fine man and excellent scientist who was claimed far too early by cancer.

Financial & competing interests disclosure

Mark R Lackner is an employee of Genentech, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.