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The molecular landscape and biological alterations induced by PRAS40-knockout in head and neck squamous cell carcinoma.

ABSTRACT: PRAS40 (Prolin-rich Akt substrate of 40 kDa) is a critical protein that directly connects PI3K / Akt and mTORC1 pathway. It plays an indispensable role in the development of many diseases. However, the relationship of PRAS40 and head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, our study indicated that high expression of PRAS40 mRNA is a favorable prognosis factor in HNSCC patients by analyzing 498 clinical and mRNA data. Moreover, we confirmed that CRISPR/Cas9 induced PRAS40-knockout would promote cell colony formation, migration, and invasion in several HNSCC cell lines. RNA-seq was employed to investigate the further possible mechanisms involving in the above regulations by PRAS40 in HNSCC cells. The molecular landscape contributed by 253 differential expressed mRNA after PRAS40-knockout were enriched in TGF-beta, PI3K-Akt, P53, mTOR, NF-kB signaling pathway. Partial molecular alternations within these pathways were validated by PCR or western blot. Besides, we found that high expression of PRAS40 in HNSC patients would present more CD8+ T and T follicular helper cells, but less Th17 cells than the patients with low expression of PRAS40. The altered molecular pathways and immune infiltrating cells might associate with the mechanism of PRAS40 being a suppressor in HNSCC cells, which would provide a potential prognosis predictor and therapeutic target in HNSCC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163613 | GEO | 2020/12/22

REPOSITORIES: GEO

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Project description:Introduction: The clinical benefit of EGFR tyrosine kinase inhibitor (TKI) treatment in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations is temporary, as virtually all patients develop acquired EGFR TKI resistance that occurs via diverse mechanisms. Here, we identified increased FGFR1 expression as such a resistance mechanism and using pathways analysis and drug combination testing we identified a novel combination treatment to control growth of these resistant tumors. Methods: Novel erlotinib-resistant NSCLC cell lines were generated and analyzed by mass spectrometry-based proteomics to identify altered pathways associated with erlotinib resistance. The altered pathways were further analyzed in gefitinib and osibenib resistant cell lines. Small molecule inhibitor combinations were used to block the altered pathways and investigate growth reduction in vitro and in two xenograft mouse models. FGFR1 mRNA levels were examined in pre- and (post?)- EGFR TKI treatment clinical tumor samples. Results: Proteomic analysis revealed increased expression of FGFR1 and AXL as well as increased Akt and ERK1/2 activation in a panel of novel erlotinib-resistant HCC827 cell lines. Combined treatment with erlotinib or osimertinib and a panel of small molecule inhibitors targeting AXL/MET, FGFRs, Akt, PI3K/mTOR, MEK or ERK1/2 showed that the most prominent re-sensitization to EGFR TKI occurred with the pan-FGFR inhibitor, PD173074. Interestingly, simultaneous blockade of components of the Akt pathway using specific Akt or dual PI3K-mTOR inhibitors combined with inhibitors targeting the FGFR family exhibited the most efficient growth inhibition of FGFR1 overexpressing EGFR TKI-resistant cell lines. Phosphorylation of proteins downstream of Akt, including PRAS40, FOXO and S6 ribosomal protein, were completely abrogated by PD173074 combined with the Akt inhibitor GSK2141795 . Combination treatment with PD173074 and an Akt inhibitor exhibited synergistic growth inhibition in vivo in two FGFR1 overexpressing NSCLC EGFR TKI-resistant animal models. Conclusion: The significant growth inhibition in vitro and in vivo observed with PD173074 combined with Akt compared to either drug alone imply that inhibition of several key targets may be beneficial in controlling erlotinib-resistant NSCLC. The complete abrogation of PRAS40, FOXO and S6 phosphorylations by PD173074 combined with an Akt inhibitor indicates that the Akt pathway is no longer active.

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The molecular landscape and biological alterations induced by PRAS40-knockout in head and neck squamous cell carcinoma.

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