1. Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer.
- Author
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Amato, Luisa, Omodei, Daniela, De Rosa, Caterina, Ariano, Annalisa, Capaldo, Sara, Tufano, Camilla Carmela, Buono, Rossella, Terlizzi, Cristina, Nardelli, Anna, Del Vecchio, Vitale, Palumbo, Rosanna, Tuccillo, Concetta, Morgillo, Floriana, Papaccio, Federica, Tirino, Virginia, Iommelli, Francesca, Della Corte, Carminia Maria, and De Rosa, Viviana
- Abstract
Simple Summary: Oncogene-driven non-small-cell lung cancer (NSCLC) is typically treated with targeted therapies to inhibit oncogene downstream signaling pathways and reduce tumor survival. The most common subtypes, EGFR and KRAS mutations, are amenable to these therapies; however, resistance often develops, leading to oncogene-independent metastases. This study explores non-oncogene addiction (NOA) as a novel strategy, targeting essential genes like ATR, which is involved in DNA damage response, and pyruvate dehydrogenase kinases (PDKs), which play a role in energy metabolism. Experiments were conducted using sensitive PC9 and the corresponding osimertinib-resistant cells (PC9/OR), namely EGFR-mutant H1975 and KRAS-mutant A549 cells treated with TKIs, alongside ATR and DCA inhibitors. The results indicated that combining these approaches could enhance efficacy compared to TKIs alone, suggesting a tailored strategy based on tumor subtype. This research underscores the potential of new therapeutic targets to improve treatment outcomes in patients with NSCLC compared to traditional TKI therapies. Background: Oncogene-driven NSCLC is usually treated with targeted therapies using tyrosine kinase inhibitors (TKIs) to inhibit oncogene downstream signaling pathways, affecting tumor survival and proliferation. EGFR- and KRAS-mutant NSCLCs are the most represented subtypes, and they are treated in clinical practice with oncogene-targeting drugs in the first and second line, respectively. Unfortunately, the development of oncogene-independent resistant clones limits TKI efficacy. Here, we used non-oncogene addiction (NOA) as an innovative therapeutic strategy to target other essential proteins that support changes in tumor phenotype. Specifically, we tested, for the first time, a combination of inhibitors, namely ATR, involved in DNA damage response, and pyruvate dehydrogenase kinases (PDKs), involved in energy metabolism. Methods: Sensitive PC9 and the corresponding EGFR-TKI-resistant PC9/OR, EGFR-mutant H1975, and KRAS-mutant A549 NSCLC cells, were treated with TKIs (osimertinib and selumetinib, respectively). In parallel, cells were exposed to two combination regimens: one using the TKI with an ATR inhibitor and the other one combining the two selected NOA inhibitors (ATR inhibitor, M4344; and PDK inhibitor, DCA). Results: The effect of these two combined approaches, compared to TKI alone, produced similar results in terms of cell proliferation, cell death, and migration. Thus, depending on tumor biology, selecting between the proposed therapeutic strategies will be different, to maximize tumor response. Conclusions: The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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