Oncogene additivity in the PI3K pathway in cancer

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Assistant Attending Physician-Scientist, Memorial Sloan Kettering Cancer Center
    Biography

      Neil Vasan is an Assistant Attending Physician on the Breast Medicine Service at Memorial Sloan Kettering Cancer Center. He is a physician-scientist working in the laboratory of Dr. Lewis Cantley (Weill Cornell Medical College) on oncogenic kinases and mechanisms of response to targeted therapies, with a focus on breast cancer. His work has been published in Nature and Science. He has received the NIH/NCI K08 Award, the Susan G. Komen Career Catalyst Research Award, the ASCO Young Investigator Award, and was named a 2020 AACR NextGen Star.


    Abstract

    Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.

    Learning Objectives:

    1. Understand the indications for PI3K inhibitors in breast cancer

    2. Discuss double PIK3CA mutations as a biomarker of increased response to PI3K inhibitors in breast cancer


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