Macrophage-Derived PDGF-BB and GDF-15 Promote Drug Resistance in KRAS-Mutant Colorectal Cancer

Abstract Macrophages are abundant in the colorectal tumour microenvironment and can alter drug response. Using mouse Apc/Kras/Trp53 (AKP) colorectal cancer organoids, we found that macrophages and/or macrophage-conditioned medium reduced sensitivity to the MEK inhibitor trametinib and the pan-RAS inhibitor RMC-6236. In contrast, macrophage-conditioned medium had little effect on regorafenib and increased sensitivity to dabrafenib, suggesting that resistance depends on the inhibitory profile of each drug. Secretome profiling identified PDGF-BB and GDF-15 as candidate mediators. Adding both ligands to organoid medium reproduced much of the conditioned-medium effect, whereas either ligand alone was insufficient. Inhibition of PDGFR or RET partially reduced drug resistance, suggesting that PDGF-BB and GDF-15 likely act through canonical signalling by that additional macrophage-derived signals also contribute. Kinome profiling pointed to increased tyrosine kinase signalling during trametinib treatment, with SRC family kinases emerging as a key downstream node. Consistent with this, SRC inhibition reduced the difference between control and conditioned-medium responses. The multi-kinase inhibitor masitinib—which targets several kinases along this resistance network—strongly restored sensitivity to trametinib and RMC-6236. Together, these data define a macrophage-driven resistance network in KRAS-mutant colorectal cancer organoids and support combined inhibition of RAS-pathway and tyrosine kinase signalling. Competing Interest Statement The authors have declared no competing interest.