Abstract
Phosphoinositide-3 kinase (PI3K) signaling pathway alterations occur broadly in cancer and PI3K is a promising therapeutic target. Here, we investigated acquired resistance to GDC-0941, a PI3K inhibitor in clinical trials. Colorectal cancer (CRC) cells made to be resistant to GDC-0941 were discovered to secrete amphiregulin, which resulted in increased EGFR/MAPK signaling. Moreover, prolonged PI3K pathway inhibition in cultured cells over a period of months led to a secondary loss of PTEN in 40% of the CRC lines with acquired resistance to PI3K inhibition. In the absence of PI3K inhibitor, these PTEN-null PI3K inhibitor-resistant clones had elevated PI3K pathway signaling and decreased sensitivity to MAPK pathway inhibitors. Importantly, PTEN loss was not able to induce resistance to PI3K inhibitors in the absence of amphiregulin, indicating a multimodal mechanism of acquired resistance. The combination of PI3K and MAPK pathway inhibitors overcame acquired resistance in vitro and in vivo.
Highlights
The phosphatidylinoisitol 3’-kinase (PI3K) signaling pathway can be activated by a variety of extracellular signals and is involved in cellular processes such as survival, proliferation, migration and protein synthesis [1]
The introduction of the H1047R mutation to the SW48 cell line resulted in increased cell growth and increased PI3K pathway signaling as measured by pAKTT308, pAKTS473, pPRAS40T246, pp70S6T389, and pS6S235/236
We found the parental and PI3K mutant cell lines were sensitive to the PI3K inhibitor, GDC-0941 (Supplemental Figure 1B)
Summary
The phosphatidylinoisitol 3’-kinase (PI3K) signaling pathway can be activated by a variety of extracellular signals and is involved in cellular processes such as survival, proliferation, migration and protein synthesis [1]. Aberrant activation of this pathway has been widely implicated in cancers. Two major hot spot mutations in the PI3K catalytic subunit have been reported, one in the helical domain (E545K) and the other in the kinase domain (H1047R) Both mutations are transforming and result in increased pathway signaling [2,3,4]. PI3K inhibitors offer an additional line of treatment, as with other targeted therapies, acquired resistance is likely to arise
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
