Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome
Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activ...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
19 March 2024
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| In: |
Drug resistance updates
Year: 2024, Volume: 74, Pages: 101081-1-101081-18 |
| ISSN: | 1532-2084 |
| DOI: | 10.1016/j.drup.2024.101081 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.drup.2024.101081 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1368764624000396 
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| Author Notes: | Alberto Diaz-Jimenez, Maria Ramos, Barbara Helm, Sara Chocarro, Dario Lucas Frey, Shubham Agrawal, Kalman Somogyi, Ursula Klingmüller, Junyan Lu, Rocio Sotillo |
| Summary: | Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activation of diverse mechanisms. In this study, we established mouse tumor-derived cell models representing the two most prevalent EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles to gain insights into the underlying resistance mechanisms. We showed that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance to targeted therapy. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, a protein frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells. This combination induced cell death through a multifaceted mechanism characterized by profound perturbation of the (phospho)proteomic landscape and a synergistic suppressive effect on the mTOR pathway. Our study demonstrates that the simultaneous inhibition of ALK and SRC can potentially overcome resistance mechanisms and enhance clinical outcomes in ALK-positive lung cancer patients. - One Sentence Summary - Co-targeting ALK and SRC enhances ALK inhibitor response in lung cancer by affecting the proteomic profile, offering hope for overcoming resistance and improving clinical outcomes. |
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| Item Description: | Gesehen am 18.10.2024 |
| Physical Description: | Online Resource |
| ISSN: | 1532-2084 |
| DOI: | 10.1016/j.drup.2024.101081 |