A specific genetic change called an ALK fusion causes non-small cell lung cancer (NSCLC) in some patients. This abnormality causes the ALK protein to be overactive. These tumors can be treated with ALK inhibitors, but the cancer cells quickly develop resistance. Now, in a new study, researchers from the German Cancer Research Center have demonstrated in mouse and human tumor cells that simultaneous treatment with ALK and SRC inhibitors can improve the therapeutic response of lung cancer cells and delay the development of drug resistance. This combination therapy, which strongly interferes with the protein composition of cancer cells, could improve clinical outcomes in some forms of non-small cell lung cancer. Relevant research results were recently published in Drug Resistance Updates. The paper is titled "Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome."
Specific cancer driver mutations are often found in the genome of non-small cell lung cancer, the most common lung malignancy. One of the common cancer driver mutations, called EML4-ALK, is caused by an incorrectly repaired break in the DNA strand that directly connects the ALK gene to the EML4 gene. As a result, cells produce large amounts of the continuously activated cancer-promoting kinase ALK.
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In this case, inhibitors targeting ALK could stop the cancer from growing. Unfortunately, tumor cells quickly become resistant to drugs. This continued drug-selective pressure can lead to drug-resistant changes in the ALK protein itself, but changes in other cell signaling pathways can also lead to insensitivity to ALK inhibitors. Therefore, new treatment options that can circumvent this resistance are urgently needed.
Rocio Sotillo, corresponding author of the paper and from the German Cancer Research Center, explained, "Not all EML4-ALK fusions are the same. They differ depending on the proportion of the EML4 gene that is fused." She speculated that the variants would also respond differently to ALK inhibitors. EML4-ALK variants 1 and 3 are most common in human lung tumors. In the new study, Sotillo and her team studied mouse tumor cells carrying both variants.
EML4-ALK variant 3 responds particularly poorly to ALK inhibitors. After treatment with the drug, they observed numerous changes in the proteome of the cancer cells. Surprisingly, the kinase SRC was significantly increased in drug-resistant cancer cells. They believe this shows that SRC plays a decisive role in the development of drug resistance.
They then treated cancer cells harboring EML4-ALK variant 3 with an ALK inhibitor and an SRC inhibitor simultaneously. Although one of the two inhibitors alone did not show significant inhibitory effects, their combination produced a powerful synergistic effect. This results in a significant increase in programmed cell death and reduces the ability of cancer cells to proliferate.
Figure 1. Eml4-Alk variant 1 and variant 3 show different responses to ALK inhibitors.
This also applies to patient lung cancer cells carrying the EML4-ALK fusion protein. Four patient cell lines that had become resistant to ALK inhibitors responded favorably to this combination therapy. After stopping treatment, there was almost no recurrence of tumor cells. A careful study of the cellular proteome showed that this combination therapy blocks the expression of several proteins that are upregulated in drug-resistant cancer cells, including protein components of the important cancer-driving mTOR signaling pathway.
"The combination of an SRC inhibitor and an ALK inhibitor improves the treatment response of lung cancer while delaying the emergence of drug resistance." Sotillo concluded, "This combination therapy inhibits the mTOR signaling pathway that promotes cancer development. These powerful anti-tumor effects provide evidence for further testing of this combination therapy, and may even be used as first-line therapy."
Reference
Diaz-Jimenez A, et al. Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome. Drug Resistance Updates, 2024, 74: 101081.