Biology subjects

Calzada, N.

Publications and source records attributed to Calzada, N..

3 recordsLinked to original sources

bioRxiv2026

Concomitant ablation of SOS1 and SOS2 triggers a lethal phenotype involving compromised intestinal integrity and widespread septicemia

The RAS guanine nucleotide exchange factors Son of Sevenless 1 and 2 (SOS1 and SOS2) are key regulators of RAS signaling pathways controlling cellular proliferation, differentiation, and survival processes that are essential for correct tissue homeostasis. While mice lacking both SOS1 and SOS2 die precipitously, we demonstrate herein that the combined genetic ablation of SOS1 and SOS2 triggers spontaneous, gut-derived, lethal bacteremia. Double-knockout (DKO) SOS1/2 mice exhibit extensive intestinal tissue damage, massive bacterial leakage out of the gut, and rapid progression to multi-organ failure and death. At the cellular level, loss of both SOS1 and SOS2 leads to profound immune cell depletion and a marked reduction in intestinal stem cell abundance and proliferative capacity, which is accompanied by severe disruption of intestinal architecture and increased epithelial permeability, indicating a breakdown of gut barrier integrity. Notably, therapeutic interventions aimed at enhancing cellular stemness significantly improve survival in SOS1/2 DKO mice, restoring intestinal proliferation and tissue organization. Collectively, our findings identify SOS1 and SOS2 as critical regulators of intestinal homeostasis and regenerative capacity during systemic infection and reveal stemness reinforcement as a potential strategy to overcome lethal susceptibility to sepsis.

cell biology↗

bioRxiv2025

Targeting SOS1 synergistically enhances efficacy of BCR/ABL tyrosine kinase inhibitors and overcomes resistance in chronic myeloid leukemia

ABSTRACTDisease persistence and therapeutic resistance remain a significant challenge in chronic myelogenous leukemia (CML). Here, we evaluated the therapeutic impact of SOS1 inhibition by its specific pharmacological inhibitor BI-3406 as single-agent or in combination with BCR/ABL tyrosine kinase inhibitors (TKI) like imatinib in preclinical models of CML including p210BCR/ABL mice, human CML cell lines, and patient-derived bone marrow cells. In p210BCR/ABL mice, treatment with BI-3406 or imatinib was well-tolerated in vivo after single or combined use of the drugs. Treatment with imatinib alone significantly improved survival and corrected various hematological parameters of disease burden, while the combination with BI-3406 therapy yielded even more pronounced benefits, including a substantial increase in median survival, marked reductions in peripheral white blood cell and neutrophil counts, and a notable decrease in leukemia stem cells within the bone marrow. Additionally, the combination led to further spleen size reduction and restoration of normal splenic architecture. Human CML cell lines and primary cells from CML patients subjected to combined treatment with BI-3406 and imatinib or later-generation TKI drugs showed significantly reduced proliferation and enhanced apoptosis as compared to single-agent-treated cultures, revealing a strong synergistic therapeutic behavior of the BI-3406 +TKI combinations. Remarkably, the combined treatments including BI-3406 significantly restored imatinib sensitivity in CML patient cells harboring imatinib-resistant mutations. Cellular signaling and transcriptomics profiling suggested coordinated attenuation of RAS and RAC downstream signals as a mechanistic basis for the observed therapeutic responses. Our findings highlight the synergistic therapeutic behavior of BI-3406 and underscore the benefit of SOS1 pharmacological targeting as a novel strategy enhancing efficacy and overcoming resistance to TKIs in CML.

cancer biology↗

bioRxiv2024

Pharmacological SOS1 inhibitor BI-3406 demonstrates in vivo anti-tumor activity comparable to SOS1 genetic ablation in KRAS mutant tumors

Resistance to KRASmut inhibitors frequently arises, warranting further searches for anti-RAS cancer therapies. We evaluated the tolerability and efficacy of SOS1 pharmacological inhibition in comparison to genetic ablation in different KRAS-dependent tumor settings. Contrary to the rapid lethality caused by SOS1 genetic ablation in SOS2KO mice, SOS1 pharmacological inhibition by its specific inhibitor BI-3406 did not significantly affect animal weight/viability nor cause noteworthy systemic toxicity. In BI-3406-treated KRASmut MEFs, we observed significantly reduced RAS-GTP levels and RAS downstream signaling, as well as decreased tumor burden and slower disease progression resulting from tumor-intrinsic and extrinsic therapeutic drug effects. In vivo analyses of KRASG12D allografts in immunocompromised mice and KRASG12D-driven lung adenocarcinomas in immunocompetent mice showed that systemic BI-3406 treatment impaired tumor growth and downmodulated components of the tumor microenvironment comparably to the KRASG12D inhibitor MRTX1133. Markedly stronger synergistic antitumor effects were observed upon concomitant BI-3406+MRTX113 treatment, confirming SOS1 as an actionable therapy target in RAS-dependent cancers.

cancer biology↗