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    Home > Active Ingredient News > Antitumor Therapy > Diamond mutant ALK pathway is resistant, how to choose existing targeted drugs?

    Diamond mutant ALK pathway is resistant, how to choose existing targeted drugs?

    • Last Update: 2021-08-07
    • Source: Internet
    • Author: User
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    When referring to the "diamond mutation" in non-small cell lung cancer (NSCLC), the first thing we think of is anaplastic lymphoma kinase (ALK)
    .

    ALK rearrangement is relatively rare, and three generations of targeted drugs have been developed for this target
    .

    Although the number is small, the effect is good
    .

    These excellent targeted drugs have taken lung cancer one step further from the realization of "chronic disease"
    .

    However, the development and evolution of tumors is extremely complex and changeable.
    Although the first generation of targeted drugs has more advantages and lasting effects, drug resistance is still inevitable
    .

    Starting from the root of drug resistance is the key to overcoming the resistance of targeted drugs
    .

    Through advanced molecular biology methods, researchers found that mutations in the ALK kinase region are a major cause of resistance to ALK targeted drugs, which is equivalent to a secondary mutation in the ALK pathway
    .

    Therefore, for the mutation of ALK kinase region, choosing the corresponding targeting strategy may be able to fundamentally solve the problem of drug resistance
    .

    But things are not as simple as we thought
    .

    The types of mutations in the ALK kinase region are very complex
    .

    Different individuals, different targeted drugs, and different treatment stages may produce different types of mutations
    .

    Therefore, the ALK targeting strategy after drug resistance should be optimized according to the specific mutation type and preliminary treatment plan, which also reflects the value of "individualized diagnosis and treatment"
    .

    Therefore, the researchers discussed the ALK targeting strategy and how to more accurately apply it to the clinical problems of ALK kinase-resistant non-small cell lung cancer
    .

    Clinical characteristics of ALK inhibitor resistance.
    Researchers at the University Medical Center of Groningen (UMCG) analyzed cases of non-small cell lung cancer after first-line ALK inhibitor resistance to determine ALK kinase resistance mutations, 14 of which were present Mutations in the ALK kinase region
    .

    From their detection and treatment process, we can see that the types of resistance mutations in the ALK kinase region are very complex, and the sensitivity to different targeted drug treatments is different; most patients who are resistant to crizotinib, receive aletinib and buga Treatment with tinib, ceritinib or lauratinib can achieve objective remission (Figure 1)
    .

    Figure 1 The 14 types of ALK kinase resistance mutations in the University of Groningen Medical Center receive targeted therapy.
    The data on the molecular characteristics of different ALK inhibitor resistance is UMCG.
    The sample size is relatively small, and the clinical evidence is slightly insufficient
    .

    After the ALK kinase region is resistant, which drug is most suitable? The researchers subsequently carried out a large amount of literature search, and combined the cases screened in the literature with the 14 cases of UMCG (Figure 2)
    .

    Figure 2 Research design (case selection) Researchers have observed that after any ALK inhibitor is resistant, mutations in the ALK kinase region may occur (Figure 3A)
    .

    About 80% of the samples have at least one type of mutation in the kinase region
    .

    There are more cases of ALK kinase region mutations after crizotinib resistance than second and third generation inhibitors
    .

    There are many types of mutations.
    For example, 8 kinds of mutants can appear after crizotinib resistance, and 7 kinds of mutants can appear after aletinib resistance.
    From the figure, we can see the complex characteristics of these molecular mutations.
    Sex (Figure 3B)
    .

    Even for the most common EML4-ALK fusion mutation, the frequency of resistance mutations in the same kinase region is very different for different mutant types (Figure 3C)
    .

    This shows that the probability of the occurrence of resistance in the ALK kinase region is very common, and the characteristics are complex, so individualized diagnosis and treatment is very important
    .

    Figure 3 Case characteristics of ALK drug-resistant populations.
    Existing ALK inhibitors are used to overcome mutations in the ALK kinase region.
    For each type of ALK kinase region mutations, what is the control effect of the existing ALK-targeted drugs? The researchers visually presented the results to us through the mutation-inhibitor interaction table
    .

    The green box in the figure means valid, red means invalid, and grey means insufficient evidence (Figure 4)
    .

    The researchers also compared the case with the case through in vitro experiments, and the consistency of the different mutation types was 64% to 87%
    .

    This indicates that different ALK-targeted drugs have different sensitivity to different drug-resistant mutations, and individualized diagnosis and treatment is particularly important
    .

    Figure 4 The control effect of existing ALK targeted drugs on ALK kinase resistance mutations.
    Implications Although this analysis has some shortcomings, it has given us a lot of enlightenment from the perspective of theory and clinical practice
    .

     First, there are many targeted drugs for ALK mutations, but drug resistance mutations in the kinase region may appear after application
    .

    Drug resistance is clinically manifested as the enlargement of the imaging lesions.
    Therefore, when receiving ALK-targeted drugs, if the lesions are enlarged or even progressed during the regular follow-up process, the drug resistance target should be tested as soon as possible under the guidance of the doctor.
    Testing to help determine follow-up treatment options
    .

     Second, the choice of individualized treatment is mainly based on the type of mutation in the kinase region that the patient has drug resistance, combined with other factors, such as the previous medication regimen, the patient's physical status, and the rapid progress of the disease
    .

    In clinical practice, we should communicate fully with the attending doctor, and truly participate in individualized diagnosis and treatment based on understanding the condition
    .

     Third, in addition to the mutations in the kinase region involved in drug resistance, bypass activation and tissue type switching can also cause tumor growth and drug resistance
    .

    Therefore, we should not ignore other possible resistance mechanisms
    .

    To overcome these resistance mechanisms, other treatment strategies may need to be combined
    .

     As a "diamond mutation", the development of ALK targeted drugs has indeed promoted the development of precision treatments for non-small cell lung cancer
    .

    However, in the face of complex and inevitable drug resistance at this stage, we should follow the principle of not panicking and step-by-step
    .

    It is believed that the increasing number of individualized diagnosis and treatment methods will enable lung cancer patients to obtain a better quality of life and more curative benefits
    .

     Download the Cancer Degree App to learn more about anti-cancer and anti-cancer knowledge
    .

     Reference: Actionability of on-target ALK resistance mutations in patients with non-small cell lung cancer: local experience and review of the literature.
    Clinical Lung Cancer.
    2021; https://doi.
    org/10.
    1016/j.
    cllc.
    2021.
    06 .
    011.
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