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Ref Type Journal Article
PMID (37269335)
Authors Drilon A, Sharma MR, Johnson ML, Yap TA, Gadgeel S, Nepert D, Feng G, Reddy MB, Harney AS, Elsayed M, Cook AW, Wong CE, Hinklin RJ, Jiang Y, Brown EN, Neitzel NA, Laird ER, Wu WI, Singh A, Wei P, Ching KA, Gaudino JJ, Lee PA, Hartley DP, Rothenberg SM
Title SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.
Journal Vol Issue Date Pages Journal Short Title
Cancer discovery 2023 Jun 03 OF1-OF13 Cancer Discov
URL
Abstract Text Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit.PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda.

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