Targeting mTOR/JUN/AXL Axis in TSC Tumors
Abstract
Tuberous sclerosis complex (TSC) is a disease caused by mutations in either TSC1 or TSC2. Although we know that TSC1 or TSC2 loss leads to activation of mTORC1, which drives abnormal cell behavior including tumor development, we still don’t know entirely how TSC protein loss leads to tumor development. TSC patients are commonly treated with inhibitors of the mammalian target of rapamycin (mTOR), everolimus, or rapamycin. Although helpful, these drugs typically decrease tumor size only a little, and tumors regrow quickly when patients stop taking the drugs. In addition, these drugs have side effects, which include mouth sores, high cholesterol, irritation of the lungs (interstitial pneumonitis), and delay in puberty, especially in girls. Therefore, continuous and lifelong treatment is problematic. We have recently discovered that loss of either TSC1 or TSC2 leads to activation of a pair of proteins called JUN and AXL, which are well-known in cancer from many other studies, but have not previously been connected to TSC. JUN is expressed at a higher level in TSC kidney angiomyolipomas than in any cancer type. AXL is also expressed at high levels in angiomyolipoma. Our long-term goal is to explore how TSC1/TSC2 gene mutation leads to JUN and AXL overexpression, how that triggers TSC tumor development, and whether TSC patients can benefit from inhibition of either JUN or AXL. An initial study we did in a TSC mouse model showed that kidney tumor growth was suppressed dramatically with treatment with an AXL inhibitor. More importantly, we found that AXL inhibitor significantly reduced tumor regrowth even after 2 months without treatment, but there was a dramatic tumor regrowth after Rapamycin treatment was stopped for 2 months. Our findings provide strong evidence that AXL inhibitors have promise for the treatment TSC tumors. The AXL inhibitor we used has been used for clinical trials in patients with cancer already, so that if our studies are consistent and go forward, there is potential for rapid translation to clinical trials for TSC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jun 29, 2021
- Source ID
- W81XWH2010256
Entities
People
- David J Kwiatkowski
Organizations
- United States Army