Phospho-PRAS40Thr246 predicts trastuzumab response in patients with HER2-positive metastatic breast cancer

Abstract

Resistance to trastuzumab is frequently observed during the treatment of patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancers. The aim of the present study was to determine if the phosphorylated proline-rich Akt substrate of 40 kDa (phospho-PRAS40Thr246), a novel biomarker for phosphoinositol-3 kinase (PI3K) pathway activation, could predict the response of HER2-positive metastatic breast cancers to treatment with trastuzumab. Formalin-fixed, paraffin-embedded tumor tissue samples were retrospectively collected from 55 trastuzumab-treated patients. Next, the expression of phospho-PRAS40Thr246 and phosphatase and tensin homolog (PTEN) was assessed by immunohistochemistry. In total, five common phosphoinositol-3 kinase α catalytic subunit mutations, namely E542K, E545K, E545D, H1047R and H1047L, were identified by the amplification-refractory mutation system, using the allele-specific polymerase chain reaction. The activation of the PI3K pathway, as determined by low PTEN expression or the presence of oncogenic PIK3CA mutations, was observed in 49.1% (27 cases) of the 55 HER2-positive metastatic breast cancer tissues. In total, 40% of the tumors were defined as being phospho-PRAS40Thr246-positive. Furthermore, the results revealed that phospho-PRAS40Thr246 expression was associated with the PI3K pathway activation status and an increased risk of tumor progression in HER2-positive metastatic breast cancer patients who had received trastuzumab-based therapy. Therefore, phospho-PRAS40Thr246 expression levels may reflect the PI3K pathway activation status and act as a biomarker for HER2-amplified breast cancer patients who are unlikely to respond to trastuzumab-based therapy.

Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer

“…In addition, GSK690693 significantly decreased the level of GSK3-beta, PRAS40, and several forkhead family of transcription factors, which are downstream substrates for AKT [41]. Moreover, a recent report of trastuzumabresistant HER2-positive patients showed that approximately 40% of the tumors were identified as being p-PRAS40Thr246-positive indicating that PRAS40 may be associated with increased activation of the PI3K pathway, and an increased risk of tumor progression in trastuzumab-resistant, HER2-positive metastatic breast cancer patients [20].…”

“…The aberrant activation of PI3K/AKT/mTOR pathway leads to tumor proliferation in many cancer types, including breast cancer [20,30,41]. However, it is not yet fully established whether tumor growth inhibition is clinically sustained when this cascade is therapeutically targeted, although many reports have confirmed the findings of pharmacodynamic studies using ATP-competitive and selective AKT1/2/3 inhibitors.…”

Exogenous bacterial DnaK increases protein kinases activity in human cancer cell lines

“…Several studies report that HSP27 is overexpressed in many types of cancer and its functions are mainly regulated by phosphorylation [52]. PRAS40 is a substrate of Akt, with several effects on cell metabolism including cell survival and growth [53], and it has been implicated in different pathologic conditions, including cancer and insulin resistance [54][55][56][57][58].…”

PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40 kDa (PRAS40)

“…PRAS40, a r e g u l a t o r o f m T O R p a t h w a y, w a s f o u n d t o b e hyperphosphorylated >3-fold at T246 in all 4 invasive GBC cell lines used in this study compared to the non-invasive cell line, TGBC24TKB. Hyperphosphorylation of PRAS40 has been reported in several cancers and has been indicated to play a role in cancer progression and resistance to therapy (Madhunapantula et al 2007;Kim et al 2011;Yuan et al 2015;Lu et al 2014). PRAS40 is a known substrate of AKT and PIM, which have been shown to phosphorylate PRAS40 at T246 independently.…”