(I)
Targeted drugs, while often efficacious and with high response rates in the indicated patients, are almost inevitably resistant.
What happens after drug resistance?
From the first day of using targeted drugs, this is the question every patient wants to know.
There is no single answer to this question; there are so many possibilities depending on the type of cancer, different targeted drugs, and different causes of drug resistance. All we can do is learn and try to make the choice that has the best chance of success.
Today, using ALK fusion lung cancer as an example, we will talk about the complex science behind “targeted drug resistance” and how to choose a drug.
(2)
ALK fusion gene-positive lung cancers are in the minority, but a higher proportion of patients with characteristics such as “Asian, female, nonsmoking, young, lung adenocarcinoma”.
The growth of lung cancer cells carrying ALK fusion genes is dependent on ALK protein, so drug companies have developed targeted drugs that target ALK and specifically inhibit its activity. Clinical trials have shown that these targeted drugs are significantly better than chemotherapy, both in terms of efficacy and side effects.
A simple diagram is better to understand:
The ALK fusion mutation gene, which gives a highway to cell growth signals, maintains the rapid growth of cancer cells. And ALK-targeted drugs, such as crizotinib, act as roadblocks, specifically blocking this highway. Without the growth signal, the cancer cells are “starved to death”.
Crizotinib is a first-generation ALK-targeted drug, and in clinical trials, 60% to 74% of patients had significant tumor shrinkage and almost immediate improvement in symptoms with a high quality of life.
While crizotinib is effective, patients almost invariably develop resistance between 1 and 2 years. After research, the mechanisms of resistance were found to fall into two main categories:
- Related to ALK;
- Not related to ALK.
Roughly 35% of drug resistance is ALK gene-related and 65% or so is unrelated. Here’s a separate conversation.
(iii)
Let’s start with ALK-associated drug resistance.
There are two main mechanisms of ALK-associated resistance.
The first and primary one is the emergence of new mutations in ALK that make inhibition by a generation of targeted drugs ineffective.
Another diagram:
The new ALK mutation bypassed crizotinib inhibition, allowing growth signaling to resume and cancer cells to become resistant as a result.
A variety of ALK neo-mutations have been found clinically in crizotinib-resistant patients, the first being L1196M, and later G1202R, C1156Y, L1152R, and so on. This is very different from EGFR, which is mainly just one new mutation, T790M, after EGFR mutant lung cancer is resistant to first-generation targeted drugs.
ALK patients are unfortunately fortunate because there are multiple 2nd and 3rd generation ALK-targeted drugs in the pipeline, in addition to crizotinib. These next-generation drugs are effective against many drug-resistant mutations, giving patients more options.
For example, the 2nd generation targeting drugs, ceritinib and erlotinib, have both worked well in trials for crizotinib-resistant patients, allowing 50%-60% of patients to have significant tumor shrinkage again.
Because of the different mutations after ALK resistance, this has a very important impact on the choice of subsequent drugs.
There are at least 6 subsequent ALK-targeted drugs in the clinic, each with different effects, especially for various new ALK mutations. The following table is a brief summary:
As you can see, although they are all next-generation targeted drugs, there is a difference in inhibition of different ALK resistance mutations, so it is important to resequence the ALK gene after crizotinib resistance to see if a new mutation has emerged and which one it is!
This way, it is possible to choose the next drug with the highest chance of success.
The second ALK gene-associated resistance mechanism is not because ALK is mutated, but amplified. ALK is still the same ALK, but it has become more.
Another diagram.
The highway got wider, crizotinib couldn’t be blocked, so it became resistant.
Fortunately, clinically, the next generation of targeted drugs are also effective in patients with amplified drug resistance.
(iv)
Next, let’s talk about drug resistance due to non-ALK mutations.
As I said earlier, about 65% of resistance to crizotinib is not related to ALK itself, which is neither mutated nor amplified.
In this case, the most common reason is that the cancer cells abandoned ALK and used a new signaling pathway.
Let’s take the 4th ring if the 3rd ring is blocked. Since the ALK highway is not working, let’s build another highway and go around.
EGFR, HER2, MET, MEK, PI3K, etc. are some possible alternatives to the ALK highway.
When this happens, counting on a new generation of ALK-targeted drugs just won’t do. At this point, what is needed are targeted drugs that target alternative pathways.
There is a “targeted drug rotation therapy” on the internet, which means rotating different targeted drugs, supposedly to better control tumor growth and avoid drug resistance.
There’s some truth to it, and it’s this “alternative highway” mentioned above: when one targeted drug is used, the tumor cells are likely to develop a new pathway, so if you switch to a targeted drug that targets the new pathway, it may indeed be effective and may delay the onset of drug resistance.
But the problem now is that people are rotating targeting drugs blindly. In this example in ALK-fusion lung cancer, where EGFR, HER2, MET, MEK, and PI3K are all potentially activated, which one of the targeting drugs should be chosen?
Once you choose the wrong one and block the wrong highway, it’s a waste of time and money. This is why people are now blindly rotating targeted drugs with low efficiency.
Pineapple supports the use of combinations of targeted drugs, or rotating them. But the best way to do this is not to blindly try to rotate, but to test and find out which alternative highway the cancer cells are using, so that you can use the right combination of “ALK+X” drugs.
(v)
Knowing your enemy is the only way to win a hundred battles. It can be seen that redetection of drug-resistant tumors is important, both for ALK-associated resistance and ALK-independent resistance. It is by analyzing the characteristics of new tumors that we can best avoid using the wrong drugs and delaying time and money.
Also, in addition to the above, there are other possible mechanisms of ALK resistance, such as switching cancer types and enhancing drug efflux, but the percentage is relatively low, so I won’t go into that today.
Finally, I would like to send you two reference flow charts for ALK mutant lung cancer treatment. Each patient’s situation is different, so please refer to the judgment of your treating physician.
(For newly diagnosed or after resistance to first-generation crizotinib)
(For second-generation ALK-targeted drugs after resistance)
