Uncovering Evolving Drug-resistant Cell-states in Metastatic Breast Cancer

Notwithstanding the rapidly growing armamentarium of therapeutics in metastatic malignancies
-finding therapeutic combinations that result in a durable response remains a stubbornly
intractable challenge. Thus, I dedicated my postdoctoral research to finding strategies that
may advance our understanding of this problem.
My work led to the identification of novel resistance alterations to CDK4/6 inhibition in
metastatic breast cancer (Wander*, Cohen* et al., Cancer Discovery, 2020), identification of
evolutionary acquired point mutations in HER2 as a novel resistance mechanism (Nayar,*
Cohen* et al. Nature Genetics, 2019), and acquired FGF/R pathways alterations as a prevalent
mode of resistance (Mao*, Cohen* et al. Clin Cancer Res 2020).
My ongoing work and future research are focused on studying evolved resistance while
considering both clonal dynamics (mutations) and cellular-rewiring (regulation). For this, I had
developed a schema for jointly analyzing exome and transcriptome profiles, combining both
bulk and single-cell RNA-seq profiles towards a "cell-states" outlook (representing distinctive
gene-expression and phenotypic characteristics). Recently, I had exemplified this strategy by
uncovering the transcriptional convergence in acquired resistance via activated receptor
tyrosine kinases both in-vitro and in-vivo (Cohen et al., SABCS 2019, Abstract GS2-02), and
by revealing the ER-axis transcriptional program with single-cell analysis of drug-resistant
metastatic tumors (Cohen et al., SABCS, 2019, Abstract GS6-05).

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