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HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis
Jin-Rong Guo1, Kai-Yue He1, Jia-Li Yuan1
1School of Life Sciences, Henan University, Kaifeng, Henan Province, China.
Abstract:
Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.
Insights
High mobility group AT-hook 1 (HMGA1) and FKBP12 levels predict esophageal squamous cell carcinoma (ESCC) response to mTOR inhibitors. Low HMGA1 or FKBP12 indicates resistance, while high levels suggest suitability for treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling Pathways
Background:
- Esophageal carcinoma (ESCC) is a prevalent malignancy with diverse clinical outcomes.
- The PI3K/AKT/mTOR pathway is frequently dysregulated in cancers, but resistance to mTOR inhibitors is a significant clinical challenge in ESCC.
- Understanding resistance mechanisms is crucial for effective targeted therapy.
Purpose of the Study:
- To investigate the molecular mechanisms underlying insensitivity of esophageal squamous cell carcinoma (ESCC) patients to mTOR inhibitors.
- To identify biomarkers predictive of response to mTOR inhibitor therapy in ESCC.
Main Methods:
- Assessed rapamycin sensitivity in ESCC cell lines using IC50 values.
- Utilized transcriptome sequencing to identify downstream effectors of HMGA1.
- Investigated the interaction between HMGA1 and ETS1, and FKBP12 transcription.
- Validated findings in *in vivo* xenograft models.
Main Results:
- ESCC cells with low High Mobility Group AT-hook 1 (HMGA1) levels exhibited increased tolerance to rapamycin.
- FKBP12 was identified as a crucial downstream effector of HMGA1, mediating sensitivity to rapamycin.
- HMGA1 interacted with ETS1 to facilitate FKBP12 transcription, and HMGA1 deficiency led to rapamycin resistance *in vivo*.
Conclusions:
- The HMGA1/ETS1/FKBP12 axis regulates sensitivity to mTOR inhibitors in esophageal squamous cell carcinoma.
- Reduced levels of HMGA1 or FKBP12 may predict resistance to mTOR inhibitor therapy in ESCC patients.
- Elevated HMGA1 or FKBP12 levels suggest potential suitability for mTOR inhibitor treatment in ESCC.
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