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MET as a Driver in NSCLC

Insights From: Edward B. Garon, MD, David Geffen School of Medicine at UCLA; Alexander Spira, MD, PhD, FACP, US Oncology Virginia Cancer Specialists
Published: Friday, Nov 08, 2019



Transcript: 

Edward B. Garon, MD:
MET has been an attractive target for therapy for decades, but it has been, in some respects, a frustrating target up until recently. MET was discovered as a driver decades ago, and there have been many attempts to use this as a target for interventions. There was a very large program with a MET-directed antibody that was evaluated. However, those programs looked at some specific subsets of patients and really didn’t end up showing tremendous efficacy.

In many respects, I think the initial proof of concept that MET could be appropriately targeted with drugs in non–small cell lung cancer really occurred at ASCO [American Society of Clinical Oncology] several years ago, and then subsequently published with crizotinib, which actually was originally developed as a MET inhibitor but then transitioned as an ALK inhibitor. And now of course, the drug is approved for ALK gene-rearranged and ROS1-rearranged lung cancer.

It originally was evaluated as a MET inhibitor, and it was evaluated in a small subset of patients with lung cancer who had amplification of the MET gene. It has been known, in looking at cell line panels and different tissue specimens, that there are some mutations in MET. There are some cases for which MET is amplified at the gene level.

In patients with high levels of amplification, there was evidence of activity of crizotinib. This has led to the idea that in patients who have high MET via amplification, that this would be a potential target. And there are now other studies that have looked at MET amplification as a potential driver. But in many respects, it appears that MET amplification is a more minor driver compared to the MET exon 14 skipping mutation, which has been appreciated more recently. Earlier, when I mentioned MET mutations, these were generally mutations in the exome, or in the protein coating portion of the DNA. Traditionally, we have looked for mutations in the exome. The idea was that if you were going to have an oncogene that is driving the tumor, the alterations that would make it drive a tumor would need to be in protein coating regions so that you would have an alteration to the protein.

Of course, now understanding the biology better of the MET exon 14 skipping mutation, we realize that isn’t necessarily the case. It turns out that MET exon 14 skipping mutations generally do not occur in portions of the DNA, but actually are intronic and basically prevent a certain exon from being spliced into the eventual protein—the product of exon 14.

The reason that this leads to a high activation of MET is that this is a portion of the protein that is integral in destruction of the MET protein. And so, what happens with this mutation is that you basically do not splice in a piece of RNA, which makes an eventual piece of the protein that is important for destruction of the protein. On a functional level, it is similar to amplification of the protein, being that rather than having too much, you have the inability to get rid of the protein, which ends up resulting in having more protein left—more MET protein. Theoretically, of course, it was a thought that you would be able to then target this with therapies that are directed against MET, and now we do have the first sets of clinical data that indicate that this is, in fact, a potential target for inhibitors of MET.


Transcript Edited for Clarity
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Transcript: 

Edward B. Garon, MD:
MET has been an attractive target for therapy for decades, but it has been, in some respects, a frustrating target up until recently. MET was discovered as a driver decades ago, and there have been many attempts to use this as a target for interventions. There was a very large program with a MET-directed antibody that was evaluated. However, those programs looked at some specific subsets of patients and really didn’t end up showing tremendous efficacy.

In many respects, I think the initial proof of concept that MET could be appropriately targeted with drugs in non–small cell lung cancer really occurred at ASCO [American Society of Clinical Oncology] several years ago, and then subsequently published with crizotinib, which actually was originally developed as a MET inhibitor but then transitioned as an ALK inhibitor. And now of course, the drug is approved for ALK gene-rearranged and ROS1-rearranged lung cancer.

It originally was evaluated as a MET inhibitor, and it was evaluated in a small subset of patients with lung cancer who had amplification of the MET gene. It has been known, in looking at cell line panels and different tissue specimens, that there are some mutations in MET. There are some cases for which MET is amplified at the gene level.

In patients with high levels of amplification, there was evidence of activity of crizotinib. This has led to the idea that in patients who have high MET via amplification, that this would be a potential target. And there are now other studies that have looked at MET amplification as a potential driver. But in many respects, it appears that MET amplification is a more minor driver compared to the MET exon 14 skipping mutation, which has been appreciated more recently. Earlier, when I mentioned MET mutations, these were generally mutations in the exome, or in the protein coating portion of the DNA. Traditionally, we have looked for mutations in the exome. The idea was that if you were going to have an oncogene that is driving the tumor, the alterations that would make it drive a tumor would need to be in protein coating regions so that you would have an alteration to the protein.

Of course, now understanding the biology better of the MET exon 14 skipping mutation, we realize that isn’t necessarily the case. It turns out that MET exon 14 skipping mutations generally do not occur in portions of the DNA, but actually are intronic and basically prevent a certain exon from being spliced into the eventual protein—the product of exon 14.

The reason that this leads to a high activation of MET is that this is a portion of the protein that is integral in destruction of the MET protein. And so, what happens with this mutation is that you basically do not splice in a piece of RNA, which makes an eventual piece of the protein that is important for destruction of the protein. On a functional level, it is similar to amplification of the protein, being that rather than having too much, you have the inability to get rid of the protein, which ends up resulting in having more protein left—more MET protein. Theoretically, of course, it was a thought that you would be able to then target this with therapies that are directed against MET, and now we do have the first sets of clinical data that indicate that this is, in fact, a potential target for inhibitors of MET.


Transcript Edited for Clarity
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