Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

Abstract

We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2 + cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.signaling | targeted therapy P I3K transmits signals from ligand-activated receptor tyrosine kinases (RTKs) to intracellular molecules that regulate growth, metabolism, cell size, motility, and survival. In turn, PI3K catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate to produce the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) (1, 2). Several pleckstrin homology domaincontaining proteins, including AKT and PDK1, bind to PIP3 at the plasma membrane. Phosphorylation of AKT at T308 by PDK1 and at S473 by a complex involving mTOR/Rictor (i.e., TORC2) results in the full activation of this enzyme. AKT facilitates survival and cell cycle entry by phosphorylation of proteins including GSK3α/β, FoxO transcription factors, MDM2, BAD, and p27 KIP1 (3). In addition, AKT regulates protein synthesis and cell growth via activation of the mTOR/Raptor (i.e., TORC1) complex (4, 5).PI3K/AKT is arguably the most commonly altered pathway in human cancers (6, 7). Gain-of-function mutations in PIK3CA, the gene encoding the class I A PI3K catalytic subunit p110α, are frequently present in multiple human tumors (8). Second, the PIP3 phosphatase PTEN is a tumor suppressor frequently inactivated by mutation, gene deletion, and promoter methylation (9). Further, PI3K is potently activated by oncogenes like mutant Ras and tyrosine kinases such as Bcr-Abl, HER2 (ErbB2), MET, and KIT, among others (1). Therefore, a large group of tumors with molecular alterations in the PI3K/AKT pathway is therapeutically targetable with PI3K inhibitors.Several PI3K pathway antagonists have been developed. These include ATP mimetics that bind reversibly in the ATP...

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

“…Furthermore, the use of SFK inhibitors and/or FGFR inhibitors may sensitize resistant tumors to EGFR inhibition, at least in part, by suppressing PTEN phosphorylation. The finding that FGFRs phosphorylate PTEN is interesting in the context of recent observations that coactivation of multiple receptor tyrosine kinases (RTKs) is an important mechanism of resistance to TKIs in GBM cells, and that treatment of breast and lung cancer cell lines with PI3K or EGFR inhibitors induces transcription of several RTKs, including FGFR2 and -3 (20,(35)(36)(37). The signaling connection between FGFRs and PTEN may be of particular interest in those malignancies that frequently harbor activating mutations in FGFR, such as cancers of the breast, bladder, and endometrium (38).…”

PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1

“…In fact, whereas GDC-0941 treatment results in inhibition of both ERK and AKT activation, RAS activity was modestly increased. Although more studies are needed to elucidate the feedback mechanism leading from PI3K inhibition to RAS activation, it is possible that PI3K/AKT inhibition releases a negative feedback on receptor tyrosine kinases (RTKs) that, in turn, stimulate RAS (11,14,22,23). Additionally, other regulators of RAS activation may be regulated by PI3K, such as a RAS-GAP that contains a PH domain (24).…”

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…SAR245408 is an ATP-competitive reversible PI3K inhibitor. [84,85] It has been studied as a single agent in adults with advanced malignancies, in combination with erolitinib in adults with advanced solid tumors, and in combination with paclitaxel and carboplatin in adults with advanced solid tumors. [86][87][88] Side effects included rash, nausea, vomiting, allergic reactions, and diarrhea.…”