Transcriptomic profiling of bone marrow cells from CML mouse models and newly diagnosed patients treated with SOS1 inhibitor BI-3406 and/or imatinib

Despite the success of BCR-ABL1 tyrosine kinase inhibitors (TKIs) like imatinib in treating chronic myeloid leukemia (CML), therapeutic resistance and disease persistence remain significant challenges. This study investigated the potential of BI-3406, a selective SOS1 inhibitor (a key activator of RAS signaling), either alone or in combination with imatinib. Using preclinical CML models, including transgenic mice and patient samples, it was observed that BI-3406 and imatinib administration were well-tolerated. Although both drugs partially reduced splenomegaly and leukocytosis individually, combination therapy showed a significantly greater therapeutic effect. This combination extended survival, normalized spleen architecture, and sharply reduced leukemic stem and progenitor cells, suggesting a synergistic impact on leukemic burden and stem cell compartments. In vitro assays confirmed that BI-3406 potentiated the cytotoxic effects of imatinib in CML cell lines, increasing apoptosis. Notably, in primary bone marrow cells from patients with the imatinib-resistant T315I mutation, BI-3406 not only synergized with ponatinib but also restored sensitivity to imatinib, offering a potential strategy to overcome drug resistance. RNA sequencing revealed that BI-3406 alone triggered a compensatory anabolic transcriptional program, while imatinib suppressed key proliferative and metabolic pathways. However, combination therapy produced more profound reprogramming, simultaneously reinforcing anti-proliferative effects and activating immune and inflammatory pathways. These conserved effects across murine and human samples support the translational potential of this dual-targeting strategy. In conclusion, SOS1 inhibition with BI-3406, in combination with TKIs, dismantles oncogenic signaling, suppresses leukemic stemness, and reprograms the immune microenvironment. This dual-targeting approach holds promise as a novel therapeutic strategy to enhance TKI efficacy and overcome resistance in CML.