Disruption of the ALK tumor cell proteome by concurrent inhibition of ALK and SRC kinases.

ABSTRACT: Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, refractory tumors with compound mutations or diverse resistance mechanisms remain an unmet clinical need. In this study, we established mouse tumor-derived cell models representing the most common EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles. We demonstrated that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, which is frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects on both ALK-driven murine tumor growth and ALK-patient-derived cells. This death mechanism is attributed to the profound perturbation of the (phospho)proteomic landscape, together with a synergistic suppressive effect on the mTOR pathway. Taken together, our study identifies the inhibition of ALK and SRC cells and may offer a promising strategy to overcome resistance mechanisms and improve clinical outcomes in ALK-positive lung cancer patients.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Marcel Schilling  

LAB HEAD: Prof. Ursula Klingmüller

PROVIDER: PXD043012 | Pride | 2024-04-11

REPOSITORIES: Pride