CAF-released galectin 1 mediates non-cell-autonomous resistance to ceritinib in NSCLC.

Research Square (Research Square)(2023)

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Abstract
Abstract Background Despite the advent of second and third-generation compounds targeting ALK in ALK-addicted Non-Small Cell Lung Cancer (NSCLC), this tumor remains largely incurable due to drug resistance. A variety of cell-autonomous mechanisms have been shown to mediate acquired resistance to ALK tyrosine kinase inhibitors (TKIs); however, if and how tumor stroma can drive resistance to ALK inhibitors is not known. Methods We generated in vivo NSCLC models of acquired resistance to the ALK TKI ceritinib. Mechanisms of resistance have been investigated on ex-vivo derived tumor cells and Cancer Associated Fibroblasts (CAFs). Results Here we show that, under in vivo prolonged treatment with ceritinib, CAFs increased expression and release of galectin 1 (GAL1) that, through the activation in cancer cells of EGFR-dependent signaling, sustained drug resistance. Block of stromal GAL1 or pharmacological targeting of EGFR, in combination with ALK inhibition, resulted in bypass of resistance. We also proved that this non-cell-autonomous, adaptive resistance can evolve into a cell-autonomous genetic one, thus representing an intermediate step toward acquisition of a stably resistant phenotype. Importantly, this adaptive resistance mechanism was confirmed in NSCLC patients progressed on ALK TKIs, proving the clinical relevance of our findings. Conclusions Our work underlines the importance to mechanistically understand the tumor–stroma crosstalk, that can lead to aberrant molecular signaling networks sustaining resistance to ALK inhibitors. Indeed, the reported results open novel scenarios in the design of rational clinical trials, suggesting the benefit of combining ALK TKIs with anti-EGFR treatment to overcome or even prevent ceritinib resistance onset.
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Key words
galectin,ceritinib,nsclc,caf-released,non-cell-autonomous
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