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Scott A. Foster, Christiaan Klijn, Shiva Malek  Trends in Cancer 

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Presentation on theme: "Scott A. Foster, Christiaan Klijn, Shiva Malek  Trends in Cancer "— Presentation transcript:

1 Tissue-Specific Mutations in BRAF and EGFR Necessitate Unique Therapeutic Approaches 
Scott A. Foster, Christiaan Klijn, Shiva Malek  Trends in Cancer  Volume 2, Issue 12, Pages (December 2016) DOI: /j.trecan Copyright © 2016 Elsevier Inc. Terms and Conditions

2 Figure 1 Overview of KRAS, EGFR, and BRAF Mutational Patterns in Large Cancer Genomics Data Sets. (A) Proportional bar graph showing the spectrum of codon mutations in KRAS in lung, colorectal and pancreatic cancer in The Cancer Genome Atlas data (TCGA). (B) Lollipop plot showing the distribution of mutations over the EGFR protein as seen in lung cancer or glioblastoma TCGA data. (C) Proportional bar graph of the same data in (B), but categorized as extracellular (before the 621st amino acid) or intracellular (after the 621st amino acid). Samples that presented with mutation in both regions were annotated as ‘both’. (D) Proportional bar graph showing the spectrum of codon mutations in BRAF in lung, colorectal, skin, and thyroid cancer in TCGA data. (E) Overview of BRAF mutations in Foundation Medicine data of pancreatic cancer (n=1305) [6]. TCGA data was collected from cbioportali and the provisional data sources were used where applicable. Trends in Cancer 2016 2, DOI: ( /j.trecan ) Copyright © 2016 Elsevier Inc. Terms and Conditions

3 Figure 2 Activation Mechanism and Inhibitor Sensitivity of Different BRAF Alterations Identified in Varying Tumor Types. (A) Dynamic conformational changes are required for kinases to shift between ‘on’ and ‘off’ states. In normal signaling, these shifts are controlled by upstream signaling inputs. In cancer, these conformational dynamics can be hijacked by oncogenic alterations shifting the kinase towards the ‘on’ state. One of these critical shifts is the movement of the αC-helix (labeled αC) from an ‘out’ conformation (shifted away from the β3 strand; labeled β3) in the ‘off’ state inwards (towards the β3 strand) in the ‘on’ state. This shift forms critical interactions between β3 and αC, allowing the proper coordination of ATP required for kinase activity. The ability of the kinase to toggle between these two states is afforded by the flexibility of the β3–αC loop. In the β3–αC deletions, this loop is shortened effectively locking the kinase in the ‘on’ conformation. (B) BRAF mutant melanomas largely consist of BRAF V600E mutations. These mutations confer monomeric kinase activity, allowing the kinase to accommodate both the αC ‘out’ inhibitor vemurafenib (shown in red) and αC ‘in’ inhibitors (shown in green). (C) BRAF mutant lung adenocarcinomas largely consist of BRAF noncanonical kinase domain point mutations. These mutations promote dimerization, which induces the shift of αC towards the ‘in’ conformation. While these alterations show sensitivity to αC ‘in’ inhibitors, they show decreased sensitivity to the αC ‘out’ inhibitor vemurafenib. (D) BRAF mutant pancreatic adenocarcinomas largely consist of BRAF β3–αC deletions. The shortening of this loop results in monomeric kinase activity, but locks the kinase in the αC ‘in’ conformation. These deletions are resistant to the αC ‘out’ inhibitor vemurafenib, while remaining sensitive to αC ‘in’ inhibitors. Model figures were generated with the assistance of Allison Bruce. Trends in Cancer 2016 2, DOI: ( /j.trecan ) Copyright © 2016 Elsevier Inc. Terms and Conditions


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