Pharmacodynamics of malignant mesothelioma MSTO-211H dn-TEAD2 xenograft recurrence.

We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, expression of a doxycycline-dependent dominant negative TEAD2 temporarily modulates YAP1/TEAD-dependent gene expression and inhibits growth of established tumor xenografts. Recovery of tumor growth is associated with TEAD-dependent transcription comparable to untreated tumors, therefore, re-activation of TEAD transcription complexes. Human malignant mesothelioma MSTO-211H cells transfected with a doxycycline-dependent dominant negative-TEAD2 (dn-TEAD2) construct were inoculated subcutaneously in mice and allowed to grow to about 300 mm3 under glucose supplementation. At time 0, the mice were split into groups receiving doxycycline or not. After a short but significant inhibition of xenograft growth by doxycycline, the tumors in treated animals regained growth rates comparable to untreated controls. We followed transcription at the end of the experiment when all untreated, and fully, or partially treated xenografts grew at similar rates.