Webster K. Cavenee
Dr. Cavenee’ scurrent interests include the malignant progression of astrocytic(brain) tumours, the role of DNA methylation in tumor initiation, the differentiation pathways of astrocytes and the role of fusion transcription factors in paediatricneoplasms.
Abstract
Intratumoral genetic heterogeneity contributes to cancer drugResistancebut the underlying mechanisms are poorly understood. We used single cell analyses of patient-derived cell cultures, xenografts and tissue from glioblastoma patients to make the surprising observation that tumor cells reversibly up regulate or suppress oncogene expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Acquired resistance to EGFR tyrosine kinase inhibitor (TKI) is mediated by elimination of EGFR from extrachromosomal DNA.
After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results demonstrate a highly specific, dynamic, and adaptive means by which cancers can evade targeted therapies directed at oncogenic drivers carried on extrachromosomal DNA.
Background
In cancer, mutations in proteins that control cell growth are common, leading toun restrained cellular proliferation and tumor formation. The epidermal growth factor receptor (EGFR) is one such protein. Dr. Cavenee and his team found a unique mechanism by which glioblastoma cells develop resistance to drugs that target EGFR signaling. They found instead of mutation, the cells accomplished this feat by hijacking the signaling of perfectly normal cellsurface receptor named platelet-derived growth factor-β(PDGFRβ). In their laboratory models, through targeting both receptors at once, they successfully prevent resistance and suppress glioblastoma tumors. Dr. Cavenee’ s research findings high⁃light the remarkable adaptability of cancer cells and how they harness multiple mechanisms to maintain the growth signals critical to their survival. These results also point to a specific mechanism of resistance that can be anticipated and potentially targeted. Further, other types of cancer could potentially develop this type of resistance mechanisms.(Edited by Yichu Ye, some information from Dr. Cavenee's published papers)
