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• W4383373721 abstract "<div><p>NF1 is a key tumor suppressor that represses both RAS and estrogen receptor-α (ER) signaling in breast cancer. Blocking both pathways by fulvestrant (F), a selective ER degrader, together with binimetinib (B), a MEK inhibitor, promotes tumor regression in NF1-depleted ER⁺ models. We aimed to establish approaches to determine how NF1 protein levels impact B+F treatment response to improve our ability to identify B+F sensitive tumors. We examined a panel of ER⁺ patient-derived xenograft (PDX) models by DNA and mRNA sequencing and found that more than half of these models carried an <i>NF1</i> shallow deletion and generally have low mRNA levels. Consistent with RAS and ER activation, RET and MEK levels in NF1-depleted tumors were elevated when profiled by mass spectrometry (MS) after kinase inhibitor bead pulldown. MS showed that NF1 can also directly and selectively bind to palbociclib-conjugated beads, aiding quantification. An IHC assay was also established to measure NF1, but the MS-based approach was more quantitative. Combined IHC and MS analysis defined a threshold of NF1 protein loss in ER⁺ breast PDX, below which tumors regressed upon treatment with B+F. These results suggest that we now have a MS-verified NF1 IHC assay that can be used for patient selection as a complement to somatic genomic analysis.</p>Significance:<p>A major challenge for targeting the consequence of tumor suppressor disruption is the accurate assessment of protein functional inactivation. NF1 can repress both RAS and ER signaling, and a ComboMATCH trial is underway to treat the patients with binimetinib and fulvestrant. Herein we report a MS-verified NF1 IHC assay that can determine a threshold for NF1 loss to predict treatment response. These approaches may be used to identify and expand the eligible patient population.</p></div>" @default.
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• W4383373721 date "2023-07-26" @default.
• W4383373721 modified "2023-09-25" @default.
• W4383373721 title "Data from Proteogenomic Approaches for the Identification of NF1/Neurofibromin-depleted Estrogen Receptor–positive Breast Cancers for Targeted Treatment" @default.
• W4383373721 doi "https://doi.org/10.1158/2767-9764.c.6729507" @default.
• W4383373721 hasPublicationYear "2023" @default.
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