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Role of the MAP Kinase Pathway in NSCLC

Insights From: Roy S. Herbst, MD, PhD, Yale Cancer Center; Bruce E. Johnson, MD, Dana-Farber Cancer Institute; Mark A. Socinski, MD, Florida Hospital Cancer Institute
Published: Wednesday, Jan 04, 2017


Transcript:

Bruce E. Johnson, MD:
The aberrant signaling in non–small cell lung cancer is a common pathway for those that have activated oncogenic drivers. So, for instance, EGFR-mutant—as well as ALK and ROS1 rearranged—tumors will signal through the MAP kinase pathway. The part that’s somewhat unusual about the BRAF-mutants is that the BRAF gene is a serine/threonine kinase instead of a receptor tyrosine kinase, which is what’s present for the other 3 that I’ve talked about. And this serine/threonine kinase, you can directly inhibit the activity by treating it with dabrafenib. The activation, the BRAF pathway, also increases the signaling of MEK, which is downstream in the MAP kinase pathway. And you can develop a drug or you can use a drug called trametinib or another MEK kinase inhibitor that can also inhibit that pathway. So, you can attack the pathway at 2 different points and have a synergistic effect on the antitumor activity.

Mark A. Socinski, MD: Over the past several years, we’ve understood that there are a number of different pathways that have molecular alterations that lead to an oncogenic driver situation. The RAS, RAF, MEK kinase pathways are some of them. And so, understand that particularly in the instance of RAF mutations, particularly BRAF, and others, these can constitutively activate this pathway. It becomes an oncogenic driver, and therefore, it becomes a target for specific targeted agents that will inhibit this particular pathway. And I think we’ve seen a number of examples, not only BRAF, but EGFR mutations, ALK translocations, ROS1, and others, in which you have a molecular alteration that turns the light switch on, if you will, the light switch of driving the growth of the cancer. By specific targeted agents inhibiting these kinases, you can have much more dramatic results than we’ve typically seen with what I would call “nonspecific chemotherapy.”

Roy S. Herbst, MD, PhD: Targeting MAP kinase and other pathways in lung cancer is important, and the reason why you would want to target multiple steps in the same pathway is that cancers are smart. Let’s say you target PI3 kinase, MEK or MAP kinase, or one of the other pathways, you can have redundancy in these pathways. You can have backup mechanisms. You can have resistance. So, in many cases now, we’re looking at ways to target cancers with MEK inhibitors and with PI3 kinase inhibitors. And, in some cases, we’re using them together to try to target pathways at multiple steps because we want to get to them before they lead to that final point, which is to activate growth of cells.

Bruce E. Johnson, MD: The way BRAF and MEK inhibitors work synergistically is that the BRAF inhibitors have a direct effect on the activated portion of the BRAF serine/threonine kinase, which then, in turn, activates MEK, which is in the MAP kinase pathway. And the MEK inhibitor has the capability of shutting off that pathway so the 2 can act synergistically by inhibiting BRAF as well as MEK and have a greater effect on down-regulating the MAP kinase pathway and, therefore, inhibiting the growth of the cancer.

Transcript Edited for Clarity
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Transcript:

Bruce E. Johnson, MD:
The aberrant signaling in non–small cell lung cancer is a common pathway for those that have activated oncogenic drivers. So, for instance, EGFR-mutant—as well as ALK and ROS1 rearranged—tumors will signal through the MAP kinase pathway. The part that’s somewhat unusual about the BRAF-mutants is that the BRAF gene is a serine/threonine kinase instead of a receptor tyrosine kinase, which is what’s present for the other 3 that I’ve talked about. And this serine/threonine kinase, you can directly inhibit the activity by treating it with dabrafenib. The activation, the BRAF pathway, also increases the signaling of MEK, which is downstream in the MAP kinase pathway. And you can develop a drug or you can use a drug called trametinib or another MEK kinase inhibitor that can also inhibit that pathway. So, you can attack the pathway at 2 different points and have a synergistic effect on the antitumor activity.

Mark A. Socinski, MD: Over the past several years, we’ve understood that there are a number of different pathways that have molecular alterations that lead to an oncogenic driver situation. The RAS, RAF, MEK kinase pathways are some of them. And so, understand that particularly in the instance of RAF mutations, particularly BRAF, and others, these can constitutively activate this pathway. It becomes an oncogenic driver, and therefore, it becomes a target for specific targeted agents that will inhibit this particular pathway. And I think we’ve seen a number of examples, not only BRAF, but EGFR mutations, ALK translocations, ROS1, and others, in which you have a molecular alteration that turns the light switch on, if you will, the light switch of driving the growth of the cancer. By specific targeted agents inhibiting these kinases, you can have much more dramatic results than we’ve typically seen with what I would call “nonspecific chemotherapy.”

Roy S. Herbst, MD, PhD: Targeting MAP kinase and other pathways in lung cancer is important, and the reason why you would want to target multiple steps in the same pathway is that cancers are smart. Let’s say you target PI3 kinase, MEK or MAP kinase, or one of the other pathways, you can have redundancy in these pathways. You can have backup mechanisms. You can have resistance. So, in many cases now, we’re looking at ways to target cancers with MEK inhibitors and with PI3 kinase inhibitors. And, in some cases, we’re using them together to try to target pathways at multiple steps because we want to get to them before they lead to that final point, which is to activate growth of cells.

Bruce E. Johnson, MD: The way BRAF and MEK inhibitors work synergistically is that the BRAF inhibitors have a direct effect on the activated portion of the BRAF serine/threonine kinase, which then, in turn, activates MEK, which is in the MAP kinase pathway. And the MEK inhibitor has the capability of shutting off that pathway so the 2 can act synergistically by inhibiting BRAF as well as MEK and have a greater effect on down-regulating the MAP kinase pathway and, therefore, inhibiting the growth of the cancer.

Transcript Edited for Clarity
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