Molecular landscape of FaDu xenograft tumors in mice after a combinatorial treatment with radiation and an HSP90 inhibitor identifies adaptation-induced targets.

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 pre-determined 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 a 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 Week 1 and Week 2 compared to 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 demonstrates 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.