Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition

Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition

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. 

INTRODUCTION 

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 [2-4]. The tumor suppressor protein phosphatase and tensin homologue (PTEN) acts to inhibit PI3K pathway signaling and is commonly mutated, deleted or epigenetically repressed in human cancers [5, 6]. Due to the dysregulation of the PI3K pathway in many cancers, there are increasing efforts in the development of PI3K pathway inhibitors as potential therapeutics with reports of efficacy being reported [7]. Although PI3K inhibitors offer an additional line of treatment, as with other targeted therapies, acquired resistance is likely to arise. To investigate resistance to PI3K inhibitors, it is important to examine mechanisms that are upstream of PI3K signaling. The PI3K pathway can be activated by mutations or overexpression of upstream signaling molecules in the ErbB family of receptor tyrosine kinases, such as EGFR/ErbB1, HER2/ErbB2, and HER3/ErbB3 [8-11]. EGFR ligands bind and activate the EGF receptor and include EGF, amphiregulin (AREG), βcellulin (BTC), epiregulin (EPR), transforming growth factor α (TGFα), heparin-binding EGFR-like growth factor (HB-EGF), and epigen [12]. The activation of EGFR is prevalent in cancer signaling and not only activates PI3K by recruiting the regulatory subunit, p85 [13], but also induces activation of the mitogen-activated protein kinase (MAPK) pathway by either Grb2 or Shc adaptor proteins [14]. EGFR signaling has been implicated as a mechanism of resistance to several targeted cancer therapies, such as crizotinib [15], trastuzumab [16, 17], and vemurafenib [18]. Not only has www.impactjournals.com/Genes & Cancer 114 Genes & Cancer dysregulation of EGFR conferred drug resistance, but stimulation by EGF ligands has been shown to subvert inhibition of targeted inhibitors as well [19]. Despite the amount of activity in the development of PI3K inhibitors, less is known about acquired resistance to these inhibitors. Engineered mouse models that express an activating H1047R mutation in PIK3CA have found up-regulation of c-Myc to be involved in PI3K inhibitor resistance [20]. In these studies, MET amplified tumors remained dependent on endogenous PI3K, while c-Myc amplified tumors became pathway independent. Additional studies using engineered cancer cells have also identified increases in c-Myc as well as eI4FE and Notch1 as potential mechanisms of resistance [21, 22]. GDC-0941 is an orally bioavailable inhibitor of Class I PI3K that is in clinical development for several solid tumor indications [23-25]. In these studies we investigate mechanisms of resistance to GDC-0941 in the SW48 CRC line that is wild-type for PI3Kα or harbors an oncogenic H1047R PI3Kα mutation. Parental SW48 and SW48 H1047R cells are able to overcome growth suppression by GDC-0941 by the addition of EGFR ligands. In addition, SW48 cell lines that have acquired resistance to GDC-0941 initiate secretion of the EGFR ligand AREG, which allows the cells to continue to grow and survive in the presence of GDC-0941. We also found that resistant cells lose PTEN after long-term culture, thereby increasing PI3K pathway signaling. These results may provide guidance on potential clinical treatment regimens.

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“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This article was published back in 2018 by Oncotarget and written by diversified experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
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