Objective: PIK3CA is one of the most frequently mutated oncogenes across multiple cancer types, playing a crucial role in tumorigenesis via the PI3K/AKT/mTOR signaling pathway. Understanding its genuine co-mutation landscape is essential for identifying oncogenic interactions and refining targeted therapeutic strategies. In this study, we analyzed the true functional co-mutation patterns of PIK3CA in colorectal adenocarcinoma (COAD), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD).
Method: Somatic mutation data were obtained from The Cancer Genome Atlas (TCGA). Co-mutation and mutual exclusivity analyses were performed using R (maftools). To rigorously distinguish genuine biological cooperativity from confounding background mutation rates, multivariate logistic regression models were implemented, incorporating tumor mutational burden (TMB) continuous covariate.
Results: TMB-adjusted analyses revealed distinct, robust co-occurrence and mutual exclusivity relationships across cancer types, filtering out passenger mutations. In COAD, PIK3CA mutations significantly co-occur with KRAS, suggesting a cooperative role in tumorigenesis, while maintaining strict mutual exclusivity with TP53. In STAD, PIK3CA exhibits a strong, true functional co-occurrence with the chromatin remodeling gene ARID1A, while maintaining mutual exclusivity with TP53 and CSMD3. Interestingly, in both LUAD and CESC, PIK3CA demonstrates a highly significant mutual exclusivity with the mucin gene MUC17, pointing to context-specific evolutionary trajectories.
Conclusion: These findings highlight the complex, TMB-independent molecular landscape of PIK3CA-driven tumors, emphasizing the necessity of cancer-type-specific therapeutic approaches. By utilizing robust TMB-adjusted models, this study successfully isolates true genetic interactions, providing valuable insights into potential drug resistance mechanisms and novel combination therapy strategies for PIK3CA-mutant cancers.
Perçin Pazarcı· Scientific Reports in Medici...· 0 citations
Background/Objectives: Malignant melanoma is characterized by constitutive PI3K/Akt/mTOR and MAPK activation, driving aggressive behavior and therapeutic resistance. Alpha-lipoic acid (αLA), a naturally occurring dithiol compound with an established clinical safety profile, has shown anticancer potential; however, its integrated molecular mechanisms in melanoma remain poorly defined. This study aimed to comprehensively evaluate the cytotoxic and mechanistic effects of αLA in B16F10 murine melanoma cells. Methods: Antiproliferative effects were assessed by MTT assay at four concentrations (250, 500, 750, 1000 µM) over 48 h. Protein levels of apoptotic markers (Bax, Bcl-2, Caspase-3, AIF), kinase signaling components (p-Akt, p-mTOR, p-ERK, p-JNK), ER stress markers (GRP78, GADD153/CHOP), and cell cycle regulator Wee1 were quantified by ELISA at a specifically selected sub-lethal concentration of 750 µM (inducing ~38% growth inhibition). Results: αLA dose-dependently inhibited B16F10 proliferation. At 750 µM, it triggered robust intrinsic apoptotic signaling, evidenced by a nearly 10-fold shift in the Bax/Bcl-2 ratio and greater than 9-fold Caspase-3 activation. Elevated AIF suggested profound mitochondrial stress and the potential priming of concurrent caspase-independent cell death mechanisms. αLA suppressed survival signaling by reducing p-Akt (44%), p-mTOR, p-ERK, and p-JNK. Treatment triggered lethal ER stress via GRP78 and GADD153/CHOP upregulation and upregulated Wee1, suggesting the induction of stress-responsive checkpoint signaling. The simultaneous CHOP upregulation and p-Akt suppression highlight a concurrent dysregulation of stress and survival pathways, suggesting a potential pro-apoptotic interplay. Conclusions: αLA exerts potent multi-target anticancer effects by inducing a broad spectrum of associated molecular changes, including the suppression of PI3K/Akt/mTOR and MAPK networks, induction of ER stress, engagement of cell cycle checkpoints, and activation of the mitochondrial Bax/Bcl-2/Caspase-3 axis. Importantly, these correlative findings do not establish proven pathway dependencies. Nevertheless, this concurrent dysregulation positions αLA as a potential disruptor of inter-pathway resilience underlying drug resistance.
Ömer Kokaçya, Perçin Pazarcı, H. M. Kaplan· Current Issues in Molecular...· 0 citations
