Key selelcted publications and scientific significance

Discovery of novel EGFR genomic alterations, activation mechanisms, and their clinical significance for EGFR-targeted therapy

Through a systematic analysis of glioblastoma genomic data from The Cancer Genome Atlas (TCGA), I have identified a novel exon 27 deletion mutation within the EGFR carboxyl-terminus domain (CTD). Functional validation studies have confirmed that this EGFR mutant is oncogenic, even in the absence of ligand and receptor autophosphorylation. Notably, this mutant has shown sensitivity to cetuximab, an EGFR-targeted monoclonal antibody. Subsequent investigations have further corroborated the significance of EGFR C-terminal deletion in cancer and exhibit enhanced responsiveness to EGFR-targeted monoclonal antibodies. Significantly, I have also demonstrated that an EGFR C-terminal deletion mutant identified in lung adenocarcinoma is oncogenic. This finding suggests that C-terminal deletion-mediated oncogenic activation represents an additional genomic alteration contributing to cancer development.

Mechanistic insight into cancer patient-derived EGFR mutant and their determinants as EGFR-directed therapy

In these studies, I explore the dependency on asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. I found that while wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not. Additionally, I discovered that different EGFR mutants show differential requirements for dimerization and that disruption of dimerization may be among the antitumor mechanisms of cetuximab. These findings were further confirmed by colon cancer-derived oncogenic EGFR mutants identified through whole-genome sequencing of patient samples and public databases.

Exploring novel resistant mechanisms to the EGFR-targeted drugs and their clinical

My laboratory has been at the forefront of research into the mechanisms underlying EGFR drug resistance, utilizing a diverse array of preclinical models and employing systematic approaches that encompass both genomics and pharmacogenomics. Our extensive work in this field has yielded clinically important results, leading to several patent applications and publications in journals. Briefly, we experimentally demonstrated that the T790M mutation can emerge via de novo events following treatment with erlotinib. Additionally, we showed that PC9 cells ectopically expressing the EGFR mutant become more rapidly resistant to erlotinib than parental PC9 cells through the acquisition of the T790M mutation, providing an important clue for designing therapeutic strategies to overcome drug resistance. A particularly noteworthy achievement has been our recent discovery of novel resistance mechanisms to EGFR-targeted therapies. The significance of these findings is underscored by their validation in patient samples, providing a crucial link between laboratory observations and clinical relevance. These discoveries form the conceptual foundation of our current research proposals, highlighting the translational potential of our work. With these data, we are in the process of preparing a manuscript for submission to a high-impact journal in the near future.

Multi-omics uncover novel resistance mechanisms to EGFR-Targeted therapies and their validation for clinical application Manuscript in preparation
Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation. Oncotarget, 2016
Early emergence of de novo EGFR T790M gatekeeper mutations during erlotinib treatment in PC9 non-small cell lung cancer cells. Biochemical and Biophysical Research Communications, 2018
Dual inhibition of AKT and MEK pathways potentiates the anti-cancer effect of gefitinib in triple-negative breast cancer cells. Cancers, 2021

Molecular Mechanisms of MIG6 in EGFR Negative Regulation and its genomic alterations in cancer

Our lab uncovered the novel molecular mechanisms underlying MIG6, a negative feedback inhibitor of EGFR, collaborating with Dr. Eck group in Harvard medical school. We found that EGFR phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src. This dual phosphorylation site allows Mig6 to inactivate EGFR in a manner that requires activation of the target receptor and that can be modulated by Src. Lately, we identify that the stoichiometric balance between MIG6 and EGFR is crucial in promoting EGFR-dependent oncogenic growth in various experimental model systems. In addition, a subset of ERRFI1 (the official gene symbol of MIG6) mutations exhibit impaired ability to suppress the enzymatic activation of EGFR at multiple levels. In summary, our data suggest that decreased or loss of MIG6 activity can lead to abnormal activation of EGFR, potentially contributing to cellular transformation. Thus, the mutation status of ERRFI1 and the expression levels of MIG6 can serve as additional biomarkers for guiding EGFR-targeted cancer therapies, including glioblastoma.