期刊
MOLECULAR ONCOLOGY
卷 16, 期 17, 页码 3066-3081出版社
WILEY
DOI: 10.1002/1878-0261.13213
关键词
ATP binding; KRAS(G12C); MAPK pathway; RAS-independent proliferation; resistance; sotorasib
类别
资金
- European Research Council [ERC-AG/695566]
- Spanish Ministry of Science, Innovation and Universities [RTI2018-094664-B-I00, RTC2017-6576-1]
- Autonomous Community of Madrid [B2017/BMD-3884 iLUNG-CM]
- CRIS Cancer Foundation
- Asociacion Espanola contra el Cancer (AECC) [GC166173694BARB]
- AXA Research Fund
- Programa de Atraccion de Talento of the Autonomous Community of Madrid
- Formacion de Personal Investigador (FPI) program of the Spanish Ministry of Science, Innovation and Universities
- AECC
KSR1 and KSR2 play important roles in the MAPK pathway, and overexpression of KSR1 or KSR2 can independently activate the pathway and induce cell proliferation. KSR1 requires dimerization with members of the RAF family to stimulate cell proliferation and decreases dependence on KRAS oncogenic signaling.
The kinase suppressor of rat sarcoma (RAS) proteins (KSR1 and KSR2) have long been considered as scaffolding proteins required for optimal mitogen-activated protein kinase (MAPK) pathway signalling. However, recent evidence suggests that they play a more complex role within this pathway. Here, we demonstrate that ectopic expression of KSR1 or KSR2 is sufficient to activate the MAPK pathway and to induce cell proliferation in the absence of RAS proteins. In contrast, the ectopic expression of KSR proteins is not sufficient to induce cell proliferation in the absence of either rapidly accelerated fibrosarcoma (RAF) or MAPK-ERK kinase proteins, indicating that they act upstream of RAF. Indeed, KSR1 requires dimerization with at least one member of the RAF family to stimulate proliferation, an event that results in the translocation of the heterodimerized RAF protein to the cell membrane. Mutations in the conserved aspartic acid-phenylalanine-glycine motif of KSR1 that affect ATP binding impair the induction of cell proliferation. We also show that increased expression levels of KSR1 decrease the responsiveness to the KRAS(G12C) inhibitor sotorasib in human cancer cell lines, thus suggesting that increased levels of expression of KSR may make tumour cells less dependent on KRAS oncogenic signalling.
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