2. Academic Validation
  3. SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy

  • Cancer Discov. 2023 Jun 3;OF1-OF13. doi: 10.1158/2159-8290.CD-23-0361.
Alexander Drilon 1,  Manish R Sharma # 2,  Melissa L Johnson # 3,  Timothy A Yap # 4,  Shirish Gadgeel 5,  Dale Nepert 6,  Gang Feng 7,  Micaela B Reddy 6,  Allison S Harney 6,  Mohamed Elsayed 6,  Adam W Cook 6,  Christina E Wong 6,  Ronald J Hinklin 6,  Yutong Jiang 6,  Eric N Brown 6,  Nickolas A Neitzel 6,  Ellen R Laird 6,  Wen-I Wu 6,  Anurag Singh 6,  Ping Wei 8,  Keith A Ching 8,  John J Gaudino 6,  Patrice A Lee 6,  Dylan P Hartley 6,  S Michael Rothenberg 6 8
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
  • 2 START Midwest, Grand Rapids, Michigan.
  • 3 Sarah Cannon Research Institute, Nashville, Tennessee.
  • 4 The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 5 Henry Ford Cancer Center/Henry Ford Health, Detroit, Michigan.
  • 6 Pfizer Boulder Research Unit, Boulder, Colorado.
  • 7 Early Clinical Development, Pfizer, Inc., Cambridge, Massachusetts.
  • 8 Pfizer Oncology Research and Development, La Jolla, California.
  • # Contributed equally.
PMID: 37269335 DOI: 10.1158/2159-8290.CD-23-0361
Abstract

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.

Significance: 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-153740
    99.37%, SHP2 Inhibitor