Abstract
BackgroundIn this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type.MethodsTo generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation.ResultsCell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test).ConclusionLoss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies.
Highlights
The introduction of targeted therapy has been accompanied by an intensive search for biomarkers to select patients for treatment
Everolimus inhibits the mammalian Target of Rapamycin pathway and its downstream substrates, S6K and 4EBP1, which promote cell growth, proliferation and survival [7]. mTOR can be activated by upstream pathways such as the MAPK pathway and the AKT/PI3K pathway [7]
After selecting only solid tumors and correcting for tissue of origin, the elastic net analysis identified a small number of genetic aberrations that could be associated with response: PTEN mutations, FGFR2 mutations and CDKN2A loss were associated with increased sensitivity (Table 1)
Summary
The introduction of targeted therapy has been accompanied by an intensive search for biomarkers to select patients for treatment. Several powerful biomarker-drug combinations have been introduced in the clinic, such as crizotinib in ALK mutant lung cancer and vemurafenib in BRAF V600E mutant melanoma [1, 2]. For these treatments, evident tumor regression can be observed in selected populations. Our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type
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