Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by co-targeting MEK and IGF-1R/PI3K
By J. Villanueva, A. Vultur, John T. Lee, R. Somasundaram, M. Fukunaga-Kalabis, Angela Cipolla, B. Wubbenhorst, Xiaowei Xu, P. Gimotty, D. Kee and 11 more. Cancer Cell, 2010
1,289 citations recorded by the source corpus.
Summary BRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGFR-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.
View Paper: https://www.semanticscholar.org/paper/eeefb9725316d1ef2e5524ad5766f1746f3f6470
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
- Jeffrey A. Magee
- A. Roesch
- E. Piskounova
- R. Scolyer
- S. Morrison
- Georgina V. Long
- Hubing Shi
- A. Vultur
Citations in the corpus
- The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients (2019, background): “, EGFR), resulting in bypass of ERK pathway dependence and therapeutic resistance (17, 20, 39).”
- Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. (2014, unknown): “Stable disease 54 (26) 69 (33) 46 (26) 62 (34) 8 (26) 7 (23)”
- Overcoming intrinsic multi-drug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells (2013, background): “Interestingly, we found an increase in pAKT in J/EGFPhigh cells that correlates well with our previous finding that reactivation of PI3K signaling can overcome vemurafenib’s cytotoxicity in melanoma cells (Villanueva et al., 2010).”
- Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “…through a variety of genetic mechanisms (Johannessen et al., 2010; Nazarian et al., 2010; Poulikakos et al., 2011; Poulikakos and Rosen, 2011; Villanueva et al., 2010), and we are unable to find any evidence that melanoma follows a cancer stem cell model (Quintana et al., 2010; Quintana et…”