Dataset Information

The Therapeutic Potential of the Restoration of the p53 Protein Family Members in the EGFR-Mutated Lung Cancer.

ABSTRACT: Despite the recent development of precision medicine and targeted therapies, lung cancer remains the top cause of cancer-related mortality worldwide. The patients diagnosed with metastatic disease have a five-year survival rate lower than 6%. In metastatic disease, EGFR is the most common driver of mutation, with the most common co-driver hitting TP53. EGFR-positive patients are offered the frontline treatment with tyrosine kinase inhibitors, yet the development of resistance and the lack of alternative therapies make this group of patients only fit for clinical trial participation. Since mutant p53 is the most common co-driver in the metastatic setting, therapies reactivating the p53 pathway might serve as a promising alternative therapeutic approach in patients who have developed a resistance to tyrosine kinase inhibitors. This review focuses on the molecular background of EGFR-mutated lung cancer and discusses novel therapeutic options converging on the reactivation of p53 tumor suppressor pathways.

SUBMITTER: Fregni M

PROVIDER: S-EPMC9267050 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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The Therapeutic Potential of the Restoration of the p53 Protein Family Members in the EGFR-Mutated Lung Cancer.

Fregni Matilde M Ciribilli Yari Y Zawacka-Pankau Joanna E JE

International journal of molecular sciences 20220629 13

Despite the recent development of precision medicine and targeted therapies, lung cancer remains the top cause of cancer-related mortality worldwide. The patients diagnosed with metastatic disease have a five-year survival rate lower than 6%. In metastatic disease, EGFR is the most common driver of mutation, with the most common co-driver hitting TP53. EGFR-positive patients are offered the frontline treatment with tyrosine kinase inhibitors, yet the development of resistanc ...[more]

PMID: 35806218

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Project description:There is a discrepancy in the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). Molecular markers other than mEGFR remain to be investigated to better predict EGFR-TKI efficacy. Here, 49 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received the first-generation EGFR-TKI icotinib therapy were included and stratified into 25 good-responders with a progression-free survival (PFS) longer than 11 months and 24 poor-responders with a PFS shorter than 11 months. We conducted targeted metabolomic detection and next-generation sequencing on serum and tissue samples, respectively. Subsequently, two metabolomic profiling-based discriminant models were constructed for icotinib efficacy prediction, 10 metabolites overlapped in both models ensured high credibility for distinguishing good- and poor-responders. Seven of the 10 metabolites displayed significant differences between the two groups, which belong to lipids including ceramides (Cers), lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), sphingomyelins (SMs), and free fatty acids (FAs). Briefly, LPC 16:1, LPC 22:5-1, and LPE 18:2 decreased in poor-responders, while Cer 36:1-3, Cer 38:1-3, SM 36:1-2 and SM 42:2 increased in poor-responders. In parallel, we identified 6 co-mutated genes (ARID1A, ARID1B, BCR, FANCD2, PTCH1, and RBM10) which were significantly correlated with a shorter PFS. Additionally, 4 efficacy-related metabolites (Cer 36:1-3, Cer 38:1-3, SM 36:1-2, and LPC 16:1) showed significant differences between the mutant and wild-type of 4 efficacy-related genes (ARID1A, ARID1B, BCR, and RBM10). SM 36:1-2 elevated while LPC 16:1 decreased in ARID1A, BCR, and RBM10 mutant groups compared to the wild-type groups. Cer 36:1-3 increased in the ARID1A and BCR mutant groups, and Cer 38:1-3 only rose in the ARID1A mutant group. Furthermore, we observed a causal-mediator-network-based interrelation between the 4 concurrently mutated genes and the 4 metabolites related metabolic genes in glycerophospholipid metabolism and sphingolipid metabolism pathways. This study demonstrated that lipids metabolism and concurrently mutated genes with mEGFR were associated with the icotinib efficacy, which provides novel perspectives in classifying clinical responses of mEGFR LUAD patients and reveals the potential of non-invasive pretreatment serum metabolites in predicting EGFR-TKI efficacy.

Project description:Background: Ovarian cancer (OV) is one of the common malignant tumors and has a poor prognosis. Chromobox (CBX) family proteins are critical components of epigenetic regulation complexes that repress target genes transcriptionally via chromatin modification. Some studies have investigated the function specifications among several CBXs members in multiple cancer types, however, little is known about the functions and prognostic roles of distinct CBXs family proteins in ovarian cancer. Methods: In this study, several bioinformatics databases and in vitro experiments were used to analyze the expression profiles, prognostic values, and therapeutic potential of the CBXs family (CBX1-8) in ovarian cancer. Results: It was found that higher expression of CBX3/8 and lower expression of CBX1/6/7 were detected in OV tissues. CBX2/4/5/8 were significantly correlated with individual cancer stages of OV. The expression of CBX1/2/3 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS) for OV patients, whereas the expression of other five CBXs members showed either irrelevant (CBX5 and CBX8) or inconsistent (CBX4, CBX6, and CBX7) results for both OS and PFS in OV. These results showed that only CBX3 had consistent results in expression and prognosis. Further cell experiments also showed that CBX3 promoted the proliferation of ovarian cancer cells. CBX3 was highly expressed in chemoresistant OV tissues. These results indicated that CBX3 was the most likely prognostic indicator and new therapeutic target in OV. Furthermore, gene enrichment analysis suggests that the CBXs family was primarily involved in mast cell activation and mast cell mediated immunity. Individual CBXs members were associated with varying degrees of the infiltration of immune cells, especially B cells. Finally, a high genetic alteration rate of CBXs family (39%) was observed in OV. The low methylation status of CBX3/8 in OV may be associated with their high expression levels. Conclusions: Taken together, these findings exhibited the pivotal value of CBXs family members (especially CBX3) in the prognosis and chemoresistance of ovarian cancer. Our results may provide new insight to explore new prognostic biomarkers and therapeutic targets for ovarian cancer.

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The Therapeutic Potential of the Restoration of the p53 Protein Family Members in the EGFR-Mutated Lung Cancer.

Publications

The Therapeutic Potential of the Restoration of the p53 Protein Family Members in the <i>EGFR</i>-Mutated Lung Cancer.

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