Biology subjects

Hofmann, M. H.

Publications and source records attributed to Hofmann, M. H..

6 recordsLinked to original sources

bioRxiv2026

DUSP4 knockdown in BRAF V600E mutant colorectal cancer induces cell cycle arrest and halts tumor growth

Oncogenic signaling in cancer cells is essential for proliferation, and its disruption, either through inhibition or overactivation, can provide therapeutic opportunities. Dual specificity phosphatase 4 (DUSP4), a negative regulator of the MAPK pathway that dephosphorylates ERK, has been proposed as a potential target; however, its therapeutic relevance has not been evaluated in vivo. In this study, we show that DUSP4 knock-down induces G1 cell cycle arrest and reduces proliferation in BRAFV600E-mutant and BRAF inhibitor-resistant colorectal cancer models, both in vitro and in vivo, and induces a rapid DUSP5-mediated adaptive response. While treatment achieved tumor stasis indicating disease control, it did not yield tumor regression, suggesting that DUSP4 may have limited efficacy as a monotherapy target in cancer.

genetics↗

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↗

bioRxiv2025

Pharmacological targeting of SOS1-RAS interaction triggers pancreatic β-cell proliferation and sustainably reverses diabetic hyperglycemia

Clinical studies have suggested that restoring a sufficient mass of functional {beta} cells can provide an effective treatment option for diabetes, however, it remains unclear whether this can be achieved through pharmacological stimulation of endogenous {beta}-cell proliferation. We demonstrate here that ectopic expression of a constitutively active form of Kras (KrasG12D) exclusively in pancreatic endocrine cells suppresses {beta}-cell proliferation, resulting in a dramatic reduction in {beta}-cell numbers and islet size. Conversely, we demonstrate that the potent and selective SOS1-RAS interaction inhibitor BI-3406 promotes unprecedented levels of {beta}-cell proliferation in primary human islets, both in culture and following transplantation in immunocompromised diabetic mice. Importantly, using murine models of streptozotocin-induced diabetes, we show that BI-3406 treatment restores {beta}-cell mass, leading to a gradual normalization of blood glucose and insulin levels, as well as to sustainable improvement in glucose tolerance. Our data provide the first pre-clinical evidence of an orally bioavailable KRAS inhibitor that can directly induce {beta}-cell regeneration.

cell 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↗

bioRxiv2023

SOS1 inhibition enhances the efficacy of and delays resistance to G12C inhibitors in lung adenocarcinoma

Clinical effectiveness of KRAS G12C inhibitors (G12Cis) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. We found that targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 both enhanced the potency of and delayed resistance to G12Ci treatment, but the extent of SOS1i effectiveness was modulated by both SOS2 expression and the specific mutational landscape. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. Survival of drug-tolerant persister (DTP) cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) that drive therapeutic resistance. G12Ci drug tolerant persister cells showed a 2-3-fold enrichment of TICs, suggesting that these could be a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limits the clinical effectiveness of G12Cis, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci in situ. SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. These data suggest that SOS1i could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations. SignificanceThe SOS1 inhibitor BI-3406 both inhibits intrinsic/adaptive resistance and targets drug tolerant persister cells to limit the development of acquired resistance to clinical KRASG12C inhibitors in lung adenocarcinoma cells.

cancer biology↗

bioRxiv2023

Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Efforts to improve the anti-tumor response to KRASG12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.

cancer biology↗