mTOR kinase inhibition effectively decreases progression of a subset of neuroendocrine tumors that progress on rapalog therapy and delays cardiac impairment

Inhibition of mTOR signaling using the rapalog everolimus is an FDA-approved targeted therapy for patients with lung and gastroenteropancreatic neuroendocrine tumors (NET). However, patients eventually progress on treatment, highlighting the need for additional therapies. We focused on pancreatic NETs (pNETs) and reasoned that treatment of these tumors upon progression on rapalog therapy, with an mTOR kinase inhibitor (mTORKi) such as CC-223 could overcome a number of resistance mechanisms in tumors and delay cardiac carcinoid disease. We performed preclinical studies using human pNET cells in vitro and injected them subcutaneously or orthotopically to determine tumor progression and cardiac function in mice treated with either rapamycin alone or switched to CC-223 upon progression. Detailed signaling and RNA sequencing analyses were performed on tumors that were sensitive or progressed on mTOR treatment. Approximately 57% of mice bearing pNET tumors which progressed on rapalog therapy showed a significant decrease in tumor volume upon a switch to CC-223. Moreover, mice treated with an mTORKi exhibited decreased cardiac dilation and thickening of heart valves than those treated with placebo or rapamycin alone. In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared to placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Overall design: We performed RNA sequencing analyses as an unbiased means to assess changes in gene expression. Our major goal was to identify the differences in tumor mRNAs between the CC-223- and non-CC-223 responders compared to the rapamycin alone treatment arm (Fig 5A in Orr-Asman et al manuscript). The analysis was conducted using 1 tumor each from 13 and 14 mice treated with rapamycin or switched to CC-223 respectively.

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Orr-Asman MA, Chu Z, Jiang M, Worley M, LaSance K, Koch SE, Carreira VS, Dahche HM, Plas DR, Komurov K, Qi X, Mercer CA, Anthony LB, Rubinstein J, Thomas HE