KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
Elsa B Krall1,2,3, Belinda Wang1,2,3, Diana M Munoz4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
Abstract:
Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.
Insights
Loss of KEAP1 in lung cancer cells affects responses to targeted therapies by altering reactive oxygen species and metabolism. This pathway modification may promote cancer cell survival despite MAPK signaling inhibition.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Targeted therapies inhibiting the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway show efficacy in various cancers.
- Intrinsic and acquired resistance limit the long-term effectiveness of these RTK/MAPK pathway inhibitors.
Purpose of the Study:
- To investigate mechanisms of intrinsic and acquired resistance to MAPK signaling inhibition.
- To identify genetic alterations that modulate cellular responses to RTK/MAPK pathway inhibitors.
Main Methods:
- CRISPR-Cas9 gene deletion screens were employed to identify genes affecting resistance.
- Experiments were conducted in lung cancer cell lines with various mutations (BRAF, NRAS, KRAS, EGFR, ALK).
Main Results:
- Loss of KEAP1 (kelch-like ECH-associated protein 1), a regulator of NFE2L2/NRF2, significantly modulated responses to BRAF, MEK, EGFR, and ALK inhibitors.
- KEAP1 loss abrogated the increase in reactive oxygen species (ROS) induced by RTK/MAPK pathway inhibitors.
- KEAP1 loss altered cellular metabolism, enabling proliferation independent of MAPK signaling.
Conclusions:
- Alterations in the KEAP1/NFE2L2/NRF2 pathway can promote cancer cell survival.
- The KEAP1/NRF2 pathway is a potential therapeutic target for overcoming resistance to RTK/MAPK pathway inhibitors in lung cancer.
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