Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer

Jul 26, 2024Cancer letters

Combining osimertinib with AXL and FGFR blockers improves treatment of EGFR-mutated lung cancer

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Abstract

Triple therapy with osimertinib, ONO-7475, and FGFR inhibitor BGJ398 significantly increased apoptosis in high-AXL-expressing EGFR-mutated non-small cell lung cancer cells.

FGFR1 knockdown showed strong inhibition of cell growth when combined with osimertinib and ONO-7475.
Increased expression of the pro-apoptotic factor Bim was observed with the triple therapy.
Cell viability was reduced significantly with the addition of the FGFR inhibitor BGJ398 compared to the dual therapy.
Xenograft models demonstrated that the triple therapy effectively suppressed tumor regrowth.
Initial FGFR1 inhibition may help prevent the development of resistance to osimertinib and ONO-7475.

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We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells.

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Triple combination therapy comprising osimertinib, an AXL inhibitor, and an FGFR inhibitor improves the efficacy of EGFR-mutated non-small cell lung cancer

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