Figure 5 from STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts Article Swipe

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Mutant PI3K/AKT/mTOR pathway Allosteric regulation Molecular biology Western blot Kinase Chemistry Cancer research Medicine Biology Internal medicine Gene Signal transduction Receptor Biochemistry

Leonard Buckbinder , David J. St. Jean , Trang Tieu , Brendon Ladd , Brendan J. Hilbert , Weixue Wang , Jacob T. Alltucker , Samantha Manimala , Gregory V. Kryukov , Natasja Brooijmans , Gregory Dowdell , Philip Jonsson , Michael Huff , Angel Guzman-Perez , Erica L. Jackson , Marcus D. Goncalves , Darrin D. Stuart ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/2159-8290.24474083.v1 · OA: W4388112945

The efficacy of STX-478 is similar or superior to high-dose alpelisib across PI3Kα-mutant tumor xenografts while sparing insulin resistance (p.o., oral administration; q.d., daily). A, Final tumor volume percent change is represented for GP2d, Detroit 562, NCI-H1048, and HCC1954 CDX tumors. BrCa, breast cancer. B, Tumor volumes over time from PDX models (N = 3/group) harboring PI3Kα mutations in the kinase domain (ST1056: H1047R PI3Kα), kinase and helical domains (ST1799: E542K/H1065L PI3Kα), and helical domain (ST2652: E545K PI3Kα) treated with either vehicle, STX-478, or alpelisib. Statistical significance was calculated using two-way ANOVA and Dunnett multiple comparisons tests. End-of-study tumors were harvested 4 hours after the final dose, and pAKT (S473) was analyzed by Western blot. IsoSeq analysis of a tumor from model ST1799 showed that the E542K/H1065L PI3Kα mutations are in cis. AKT and pAKT (S473) were blotted separately, and a representative vinculin blot is shown.