Dr. Lockhart on Strategies for Targeting the RAS/RAF/MEK/ERK Pathway in CRC

A. Craig Lockhart, MD, MHS
Published: Tuesday, Jan 14, 2020



A. Craig Lockhart, MD, MHS, professor and associate director for Regional and Strategic Clinical Research Affiliations, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses investigational strategies targeting the RAS/RAF/MEK/ERK pathway in colorectal cancer (CRC).

While probably not true in biology, the RAS/RAF/MEK/ERK pathway appears to be vertical in schematic drawings, says Lockhart. Research has shown that blocking 1 part of the pathway can prompt an escape mechanism to develop in another part of the pathway. For example, if MEK is blocked, an escape mechanism could develop through ERK, explains Lockhart.

Therefore, investigators are trying to develop treatment strategies that block the pathway at multiple nodes. This strategy showed success in BRAF-mutant animal models when the combination of cetuximab (Erbitux) and vemurafenib (Zelboraf) was used, says Lockhart. Subsequently, those data were reproduced in human studies with the addition of irinotecan.

Additional studies are looking at targeting EGFR and MEK simultaneously; however, dual blockade of these pathways may result in overlapping toxicities, such as skin rashes and diarrhea, adds Lockhart. Although it will be challenging to develop lasting blockade strategies due to escape mechanisms and synergistic toxicity, it is a worthwhile area of research, concludes Lockhart.
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A. Craig Lockhart, MD, MHS, professor and associate director for Regional and Strategic Clinical Research Affiliations, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses investigational strategies targeting the RAS/RAF/MEK/ERK pathway in colorectal cancer (CRC).

While probably not true in biology, the RAS/RAF/MEK/ERK pathway appears to be vertical in schematic drawings, says Lockhart. Research has shown that blocking 1 part of the pathway can prompt an escape mechanism to develop in another part of the pathway. For example, if MEK is blocked, an escape mechanism could develop through ERK, explains Lockhart.

Therefore, investigators are trying to develop treatment strategies that block the pathway at multiple nodes. This strategy showed success in BRAF-mutant animal models when the combination of cetuximab (Erbitux) and vemurafenib (Zelboraf) was used, says Lockhart. Subsequently, those data were reproduced in human studies with the addition of irinotecan.

Additional studies are looking at targeting EGFR and MEK simultaneously; however, dual blockade of these pathways may result in overlapping toxicities, such as skin rashes and diarrhea, adds Lockhart. Although it will be challenging to develop lasting blockade strategies due to escape mechanisms and synergistic toxicity, it is a worthwhile area of research, concludes Lockhart.



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