American Association for Cancer Research
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Figure S3 from Multiomic-Based Molecular Landscape of FaDu Xenograft Tumors in Mice after a Combinatorial Treatment with Radiation and an HSP90 Inhibitor Identifies Adaptation-Induced Targets of Resistance and Therapeutic Intervention

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journal contribution
posted on 2024-04-02, 07:21 authored by Michelle A. Bylicky, Uma Shankavaram, Molykutty J. Aryankalayil, Sunita Chopra, Sarwat Naz, Anastasia L. Sowers, Rajani Choudhuri, Valerie Calvert, Emanuel F. Petricoin, Iris Eke, James B. Mitchell, C. Norman Coleman

Supplemental Figure S3: IPA pathway highlights genes relevant to, Cell Migration, Angiogenesis and Morbidity or mortality for Treatment groups at Week 2 compared to Untreated Week 2. Significantly altered genes ([2-fold change, p < 0.01) are shown. White indicates no significant changes, Red indicates upregulation, Blue indicates downregulation. Black arrows indicate genes of interest. More genes exist in these pathways than are displayed, for ease of visualization only genes which showed significant changes in expression in at least 2 treatment groups are presented. Genes may be relevant to more than one pathway (PLAUR) is relevant to Organismal Death and Vasculogenesis, but to avoid redundancy is shown once.


NIH intramural research program



Treatments involving radiation and chemotherapy alone or in combination have improved patient survival and quality of life. However, cancers frequently evade these therapies due to adaptation and tumor evolution. Given the complexity of predicting response based solely on the initial genetic profile of a patient, a predetermined treatment course may miss critical adaptation that can cause resistance or induce new targets for drug and immunotherapy. To address the timescale for these evasive mechanisms, using a mouse xenograft tumor model, we investigated the rapidity of gene expression (mRNA), molecular pathway, and phosphoproteome changes after radiation, an HSP90 inhibitor, or combination. Animals received radiation, drug, or combination treatment for 1 or 2 weeks and were then euthanized along with a time-matched untreated group for comparison. Changes in gene expression occur as early as 1 week after treatment initiation. Apoptosis and cell death pathways were activated in irradiated tumor samples. For the HSP90 inhibitor and combination treatment at weeks 1 and 2 compared with Control Day 1, gene-expression changes induced inhibition of pathways including invasion of cells, vasculogenesis, and viral infection among others. The combination group included both drug-alone and radiation-alone changes. Our data demonstrate the rapidity of gene expression and functional pathway changes in the evolving tumor as it responds to treatment. Discovering these phenotypic adaptations may help elucidate the challenges in using sustained treatment regimens and could also define evolving targets for therapeutic efficacy.

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