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Deconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors
Arkaitz Carracedo1, Jose Baselga, Pier Paolo Pandolfi
1Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
Targeting mTOR complex 1 (mTORC1), which regulates general protein translation, represents one of the most attractive approaches to treating cancer, since upregulation of this pathway is a common hallmark in many tumors. Nevertheless, the use of rapamycin and its analogs in the clinic has revealed that mTORC1 pathway is embedded in a network of signaling cross-talks and feedbacks which might reduce its effectiveness in cancer. We have recently described a novel signaling feedback stemming from mTORC1 inhibition, which leads to the activation of ERK-MAPK (MAPK) pathway. The observation that MAPK is activated by rapamycin and its analogs in vitro, in mouse models, and cancer patient biopsies sets the rationale for the combined use of MAPK and mTORC1 inhibitors in cancer therapy. In this extra-view, we integrate our findings into the mTORC1 signaling network and discuss its relevance for the design of combinatorial therapies with mTORC1 inhibitors.
Insights
Targeting the mTORC1 pathway is a promising cancer treatment. However, mTORC1 inhibition activates the MAPK pathway, suggesting combination therapy with MAPK inhibitors may improve cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- mTOR complex 1 (mTORC1) pathway dysregulation is common in many cancers.
- mTORC1 inhibitors like rapamycin show promise but face challenges due to complex signaling networks.
- Rapamycin treatment can lead to feedback activation of other signaling pathways, limiting efficacy.
Purpose of the Study:
- To investigate novel signaling feedbacks resulting from mTORC1 inhibition.
- To explore the activation of the ERK-MAPK pathway upon mTORC1 inhibition.
- To provide a rationale for combining mTORC1 and MAPK inhibitors in cancer therapy.
Main Methods:
- In vitro studies of mTORC1 inhibition.
- In vivo experiments using mouse models.
- Analysis of cancer patient biopsies.
Main Results:
- mTORC1 inhibition triggers a novel signaling feedback loop.
- The ERK-MAPK pathway is activated following mTORC1 inhibition.
- This activation is observed across in vitro, in vivo, and clinical settings.
Conclusions:
- Combined inhibition of mTORC1 and MAPK pathways represents a potential therapeutic strategy.
- Understanding feedback mechanisms is crucial for optimizing cancer treatment.
- This study supports the development of combinatorial therapies targeting both mTORC1 and MAPK signaling in cancer.
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