Exploring this in multiple GEMMs may have the additional advantage of identifying genotypes that particularly respond to Enzalutamide proteasome inhibition. For instance, tumors arising from mice harboring inducible KRAS and TP53 mutations responded to bortezomib, unlike tumors from mice with mutant KRAS and wildtype TP53. We observed marked differences in survival with inducible proteasome knockdown in NSCLC xenografts expressing wild-type TP53, which is in contrast with these results. We propose that the combination with radiation may unlock the potential of proteasome inhibition to a wider range of tumor genotypes. The adoption of proteasome inhibitors in the clinic will require improvement in tumor delivery. Bortezomib yielded relatively little proteasome inhibition in our xenograft studies compared to doxycycline-induced PSMA1 shRNA knockdown. Strategies including liposomal encapsulation, which has been successfully employed for doxorubicin, or use of second-generation proteasome inhibitors such as carfilzomib, marizomib or MLN9708 may improve solid tumor penetration and proteasome inhibition. The results of proteasome inhibition in NSCLC patients treated without radiotherapy have been mixed. Proteasome inhibition was examined with concurrent chemoradiotherapy in one Phase I trial of twelve patients. In this dose escalation study, patients with pathologically documented Stage IIIA-B disease received weekly CYT 11387 carboplatin and paclitaxel, together with bortezomib 0.3�C0.7 mg/m2 twice weekly, during radiotherapy to a dose of 61.2 Gy in 34 daily fractions, followed by surgical resection. There were no unanticipated acute toxicities during chemoradiotherapy; Grade 2�C3 myelosuppression was common, as expected with carboplatin and paclitaxel. Regrettably however, three of nine patients who underwent surgical resection died postoperatively; two died two to three days postoperatively and a third died 21 days postoperatively. It was concluded that delayed toxicity was severe and unpredictable. However, all three patients had undergone a right pneumonectomy after high-dose neoadjuvant chemoradiotherapy. Right pneumonectomy following neoadjuvant therapy has been associated with significantly increased mortality risk, regardless of addition of novel systemic agents. For example, there has been a reported 18% treatment-related mortality rate after right pneumonectomy, compared to a 4% rate after left pneumonectomy, after neoadjuvant radiotherapy to a median dose of 54 Gy with concurrent chemotherapy. What was notable about the Phase I study was the high rate of pathologic complete response observed in patients treated with neoadjuvant chemoradiotherapy including bortezomib.