Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer

Abstract

Summary PIK3CA , encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER + breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13 C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[ 18 F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.

Metabolic imaging with hyperpolarized [1-13C] pyruvate in patient-derived preclinical mouse models of breast cancer

“…2020 ), as had been done previously in established cell line xenograft models of glioblastoma ( Venkatesh et al., 2012 ) and breast cancer ( Ward, Venkatesh et al. 2010 , Ros et al. 2020 ).…”

“…The technique has been used with patient-derived xenograft models of breast cancer, where we used it to detect response to PI3K alpha inhibitors ( Ros et al. 2020 ), as had been done previously in established cell line xenograft models of glioblastoma ( Venkatesh et al., 2012 ) and breast cancer ( Ward, Venkatesh et al.…”

“…We describe here an experimental protocol for using this technique in patient-derived and established cell line xenograft models of breast cancer in the mouse. For complete details on the use and execution of this protocol, please refer to Ros et al. (2020) .…”

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

“…This is occasionally determined by genetic predisposition, whereby the selection of rare pre-existing resistance-conferring genetic mutations limit overall therapy sensitivity. In some of these cases, the development of drug resistance may be mediated by loss of PTEN expression; altered expression of RSK3/4, PIM, AXL, FOXM1, NOTCH, c-MYC, PDK-1-SGK1, SGK3 and CDK4/6; or KRAS mutations [ 77 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. However, under certain contexts downregulation of the targeted pathways can result in genetically independent intrinsic compensatory mechanisms with survival rather than continued proliferation being the ultimate outcome.…”

“…This effect is possibly due to increased IR expression within the tumours, suggesting these results as likely biomarkers associated with patient responses following treatment [ 151 ]. It has also recently been reported that lactate can serve as surrogate to measure glycolytic flux and can effectively determine PI3K pathway inhibition [ 125 , 152 ].…”