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10.1016/j.bbadis.2025.168014 http://scihub22266oqcxt.onion/10.1016/j.bbadis.2025.168014 40784600!ä!40784600 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 227.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 261.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\40784600.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Biochim+Biophys+Acta+Mol+Basis+Dis 2025 ; 1871 (8): 168014 Nephropedia Template TP {{tp|p=40784600|t=2025. Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells |pdf=|usr=}}{{40784600}} gab.com Text Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells JO: Biochim Biophys Acta Mol Basis Dis http://www.kidney.de/pget.php?&tw=1&pmid=40784600 #FOAvip The metabolic reprogramming of tumor cells plays a critical role in cancer progression, contributing to drug resistance and tumor survival. Tyrosine kinase inhibitors (TKIs) have shown promising clinical results by targeting specific signaling pathways in cancer cell proliferation, survival, and metastasis and are now standard of care for NSCLC with actionable mutations. However, secondary resistance to TKIs remains a significant challenge. Here, we explored the rationale behind combining TKIs with an inhibitor of glucose metabolism (dichloroacetate, DCA), focusing on the synergistic effects from dual inhibition of oncogenic and metabolic reprogramming. We selected three NSCLC cell line models (H1975, H1993, A549) with EGFR/MET/KRAS mutations and determined the optimal DCA dose (500 muM) to reverse the Warburg effect. TKIs in combination with DCA (CI < 1, indicating synergy) altered cell metabolism, by improving oxidative phosphorylation via reduced glucose consumption (~50 %, p < 0.05) and increased ATP (~50 %, p < 0.0001), particularly mitoATP, confirmed by metabolite levels. The combination also reduced cell proliferation (S phase p < 0.001), increased cell death (~40 %, p < 0.0001 less MMP, ~1.6 fold more BIM, 2.5-fold more autophagy) and blocked invasion (~3 fold fewer protrusions). Our findings show DCA potentiates TKIs at lower doses, likely via Warburg effect reversal. These changes in tumor behaviour leads to a higher pro-apoptotic status responsible for an increased tumor response and, in parallel, the lower doses reduced alternative evasion pathways contributing to decrease of tumor invasion and resistance mechanism. This study shed light on a new potential combined therapeutic approach to improve clinical outcomes in targeted cancer therapy scenarios. Twit Text FOAVip Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells ????Biochim Biophys Acta Mol Basis Dis http://www.kidney.de/pget.php?&tw=1&pmid=40784600 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=40784600 #FOAvip English Wikipedia <ref>{{Cite pmid|40784600}}</ref> Synergistic effects of oncogene inhibition and pyruvate dehydrogenase kinase blockade in resistant NSCLC cells #MMPMID40784600 Amato L; De Rosa C; Omodei D; Tufano CC; Buono R; Tuccillo C; Roviello GN; Spinelli M; Fontanarosa C; Papaccio F; Camerlingo R; Morgillo F; Carpentieri A; Amoresano A; Tirino V; Iommelli F; Corte CMD; Del Vecchio S; De Rosa V Biochim Biophys Acta Mol Basis Dis 2025[Aug]; 1871 (8): 168014 PMID40784600show ga The metabolic reprogramming of tumor cells plays a critical role in cancer progression, contributing to drug resistance and tumor survival. Tyrosine kinase inhibitors (TKIs) have shown promising clinical results by targeting specific signaling pathways in cancer cell proliferation, survival, and metastasis and are now standard of care for NSCLC with actionable mutations. However, secondary resistance to TKIs remains a significant challenge. Here, we explored the rationale behind combining TKIs with an inhibitor of glucose metabolism (dichloroacetate, DCA), focusing on the synergistic effects from dual inhibition of oncogenic and metabolic reprogramming. We selected three NSCLC cell line models (H1975, H1993, A549) with EGFR/MET/KRAS mutations and determined the optimal DCA dose (500 muM) to reverse the Warburg effect. TKIs in combination with DCA (CI < 1, indicating synergy) altered cell metabolism, by improving oxidative phosphorylation via reduced glucose consumption (~50 %, p < 0.05) and increased ATP (~50 %, p < 0.0001), particularly mitoATP, confirmed by metabolite levels. The combination also reduced cell proliferation (S phase p < 0.001), increased cell death (~40 %, p < 0.0001 less MMP, ~1.6 fold more BIM, 2.5-fold more autophagy) and blocked invasion (~3 fold fewer protrusions). Our findings show DCA potentiates TKIs at lower doses, likely via Warburg effect reversal. These changes in tumor behaviour leads to a higher pro-apoptotic status responsible for an increased tumor response and, in parallel, the lower doses reduced alternative evasion pathways contributing to decrease of tumor invasion and resistance mechanism. This study shed light on a new potential combined therapeutic approach to improve clinical outcomes in targeted cancer therapy scenarios. äSynergistic effects of oncogene inhibition and pyruvate dehydrogenase (epmc).pdf DeepDyve Pubget Overpricing