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Targeting CPXM2-DSD enhances the sensitivity of PDAC treatment by disrupting collagen fiber alignment

ABSTRACT: 5×106 PaTu 8988t cells were spread into 10cm dish and then replaced into 5ml serum-free medium after being attached to the wall. At the same time, 5ml of the supernatant of PCAF-Ctrl, PCAF-CPXM2-WT and PCAF-CPXM2-mut stable cell strains were added to each group. After 8 hours, proteins from each group were collected for phosphorylated protein enrichment. The phosphorylated protein enrichment kit was used for this process, followed by protein mass spectrometry analysis of the signaling pathway of pancreatic cancer cells activated by collagen topology mediated by CPXM2.

ORGANISM(S): Homo Sapiens

SUBMITTER: Jun Mi

PROVIDER: PXD062248 | iProX | Wed Mar 26 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Mutant KRAS (mut-KRAS) is present in 30% of all human cancers and plays a critical role in cancer cell growth and resistance to therapy. There is evidence from colon cancer that mut-KRAS is a poor prognostic factor and negative predictor of patient response to molecularly targeted therapy. However, evidence for such a relationship in non small cell lung cancer (NSCLC) is conflicting. KRAS mutations are primarily found at codons 12 and 13, where different base changes lead to alternate amino acid substitutions that lock the protein in an active state. The patterns of mut-KRas amino acid substitutions in colon cancer and NSCLC are quite different, with aspartate (D) predominating in colon cancer (50%) and cysteine (C) in NSCLC (47%). Through an analysis of a recently completed biopsy biomarker-driven, molecularly targeted multi-arm trial of 215 evaluable patients with refractory NSCLC we show that mut-KRas-G12C/V but not total mut-KRAS predicts progression free survival for the overall group, and for the sorafenib and vandetanib treatment arms. Transcriptome microarray data shows differential expression of cell cycle genes between mut-KRas-G12C/V and G12D patient tumors. A panel of NSCLC cell lines with known mut-KRas amino acid substitutions was used to identify pathways activated by the different mut-KRas, showing that mut-KRas-G12D activates both PI-3-K and MEK signaling, while mut-KRas G12C does not, and alternatively activates RAL signaling. This finding was confirmed using immortalized human bronchial epithelial cells stably transfected with wt-KRAS and different forms of mut-KRAS. Molecular modeling studies show that the different conformation imposed by mut-KRas-G12C could lead to altered association with downstream signaling transducers compared to wild type and mut-KRas-G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRas amino acid substitutions signal to effectors in a similar way, and may require different therapeutic interventions.

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Targeting CPXM2-DSD enhances the sensitivity of PDAC treatment by disrupting collagen fiber alignment

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