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Compensatory Increase of Transglutaminase 2 Is Responsible for Resistance to mTOR Inhibitor Treatment
Jingwen Cao1,2, Wenlong Huang1
1China Pharmaceutical University, Nanjing, Jiangsu Province, People's Republic of China.
Abstract:
The mechanistic target of rapamycin complex 1 (mTORC1) plays a crucial role in controlling cell growth and homeostasis. Deregulation of mTOR signaling is frequently observed in some cancers, making it an attractive drug target for cancer therapy. Although mTORC1 inhibitor rapalog-based therapy has shown positive results in various pre-clinical animal cancer studies, tumors rebound upon treatment discontinuation. Moreover, several recent clinical trials showed that the mTORC1 inhibitors rapamycin and rapalog only reduce the capacity for cell proliferation without promoting cell death, consistent with the concept that rapamycin is cytostatic and reduces disease progression but is not cytotoxic. It is imperative that rapamycin-regulated events and additional targets for more effective drug combinations be identified. Here, we report that rapamycin treatment promotes a compensatory increase in transglutaminase 2 (TGM2) levels in mTORC1-driven tumors. TGM2 inhibition potently sensitizes mTORC1-hyperactive cancer cells to rapamycin treatment, and a rapamycin-induced autophagy blockade inhibits the compensatory TGM2 upregulation. More importantly, tumor regression was observed in MCF-7-xenograft tumor-bearing mice treated with both mTORC1 and TGM2 inhibitors compared with those treated with either a single inhibitor or the vehicle control. These results demonstrate a critical role for the compensatory increase in transglutaminase 2 levels in promoting mTORC1 inhibitor resistance and suggest that rational combination therapy may potentially suppress cancer therapy resistance.
Insights
Rapamycin inhibits cancer cell growth but causes resistance by increasing transglutaminase 2 (TGM2). Combining mTORC1 and TGM2 inhibitors promotes tumor regression, offering a new cancer therapy strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The mechanistic target of rapamycin complex 1 (mTORC1) pathway is vital for cell growth and homeostasis.
- mTOR signaling deregulation is common in cancers, making it a therapeutic target.
- mTORC1 inhibitors like rapamycin are cytostatic, not cytotoxic, leading to treatment resistance.
Purpose of the Study:
- To identify rapamycin-regulated events contributing to cancer therapy resistance.
- To investigate transglutaminase 2 (TGM2) as a potential target for overcoming mTORC1 inhibitor resistance.
- To evaluate combination therapy with mTORC1 and TGM2 inhibitors for enhanced anti-cancer effects.
Main Methods:
- Investigated the effect of rapamycin on transglutaminase 2 (TGM2) levels in mTORC1-driven tumors.
- Assessed the impact of TGM2 inhibition on sensitizing cancer cells to rapamycin.
- Examined the role of autophagy blockade in regulating TGM2 upregulation.
- Evaluated the efficacy of combined mTORC1 and TGM2 inhibition in a mouse xenograft model (MCF-7).
Main Results:
- Rapamycin treatment led to a compensatory increase in TGM2 levels in tumors.
- TGM2 inhibition sensitized mTORC1-hyperactive cancer cells to rapamycin.
- Blocking rapamycin-induced autophagy inhibited the compensatory TGM2 upregulation.
- Combination therapy with mTORC1 and TGM2 inhibitors resulted in significant tumor regression in mice.
Conclusions:
- The compensatory upregulation of TGM2 is a key mechanism of resistance to mTORC1 inhibitors.
- Inhibiting TGM2 can overcome resistance to rapamycin in cancer therapy.
- Combination therapy targeting both mTORC1 and TGM2 shows promise for suppressing cancer therapy resistance and improving treatment outcomes.
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