Critical Requirement of SOS1 for Development of BCR/ABL-Driven Chronic Myelogenous Leukemia

Abstract

We showed previously that the ABL-mediated phosphorylation of SOS1 promotes RAC activation and contributes to BCR-ABL leukemogenesis, suggesting the relevant role of SOS1 in the pathogenesis of CML. To try and obtain direct experimental evidence of the specific mechanistic implication of SOS1 in CML development, here, we combined a murine model of CML driven by a p210BCR/ABL transgene with our tamoxifen-inducible SOS1/2-KO system in order to investigate the phenotypic impact of the direct genetic ablation of SOS1 or SOS2 on the pathogenesis of CML. Our observations showed that, in contrast to control animals expressing normal levels of SOS1 and SOS2 or to single SOS2-KO mice, p210BCR/ABL transgenic mice devoid of SOS1 presented significantly extended survival curves and also displayed an almost complete disappearance of the typical hematological alterations and splenomegaly constituting the hallmarks of CML. SOS1 ablation also resulted in a specific reduction in the proliferation and the total number of colony-forming units arising from the population of bone marrow stem/progenitor cells from p210BCR/ABL transgenic mice. The specific blockade of CML development caused by SOS1 ablation in p210BCR/ABL mice indicates that SOS1 is critically required for CML pathogenesis and supports the consideration of this cellular GEF as a novel, alternative bona fide therapeutic target for CML treatment in the clinic.

Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma

“…We and others have also identified specific functional roles of SOS1 and SOS2 in different cellular contexts 9 , 22 , 26 , 29 – 31 . Regarding tumoral contexts, we have also uncovered a critical functional contribution of SOS1 for development of DMBA/TPA-induced skin carcinogenesis 32 and BCR/ABL-driven chronic myeloid leukemia 33 , 34 , thus supporting the consideration of this GEF isoform as a potentially useful therapeutic target for RAS-dependent cancers. In addition, SOS1 knockdown has also been shown to effectively enhance the therapeutic efficacy of MEK inhibitors in KRAS-amplified gastroesophageal cancer 35 and to overcome secondary acquired resistance to osimertinib in EGFR-mutated LUAD human cell lines 36 .…”

Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo

“…Coupled with the rotation of the REM domain, it allows for Ras binding and nucleotide exchange. − Activated Ras plays an important role in cell proliferation, transformation, survival, and migration, while overactivation of Ras usually accompanies oncogenesis. − Human SOS proteins include hSOS1 and hSOS2 . Abnormal or mutated SOS1 causes leukemia, , Noonan syndrome, Costello syndrome, and neurofibromatosis. − Moreover, activation of SOS1 was shown to be a key mechanism for the development of adaptive resistance to MEK inhibitors . Therefore, inhibiting SOS1 provides a different strategy to suppress the activity of RAS mutants …”

“…7−9 Human SOS proteins include hSOS1 and hSOS2. 10 Abnormal or mutated SOS1 causes leukemia, 11,12 Noonan syndrome, Costello syndrome, and neurofibromatosis. 13−16 Moreover, activation of SOS1 was shown to be a key mechanism for the development of adaptive resistance to MEK inhibitors.…”

Development of Son of Sevenless Homologue 1 (SOS1) Modulators To Treat Cancers by Regulating RAS Signaling

“…32 The depletion of SOS1 significantly increased imatinib sensitivity in chronic myelogenous leukemia (CML) cells and suppressed the development of CML in the p210 BCR/ABL mice. 33,34 Furthermore, SOS1-mimic peptides were utilized to disrupt the SOS1-RAS interfacial interaction and inhibit the subsequent RAS signaling. 35,36 Consequently, specific SOSbound molecules potentially can be employed in a broad spectrum of RAS-driven cancers, namely, as pan-RAS inhibitors.…”

“…In hematological malignancies, SOS1 deficiency attenuated oncogenic KRAS G12D -induced myeloproliferative neoplasm phenotypes and prolonged the survival of positive KRAS G12D mice . The depletion of SOS1 significantly increased imatinib sensitivity in chronic myelogenous leukemia (CML) cells and suppressed the development of CML in the p210 BCR/ABL mice. , Furthermore, SOS1-mimic peptides were utilized to disrupt the SOS1-RAS interfacial interaction and inhibit the subsequent RAS signaling. , Consequently, specific SOS-bound molecules potentially can be employed in a broad spectrum of RAS-driven cancers, namely, as pan -RAS inhibitors. − To date, two SOS1 inhibitors, BI 1701963 from Boehringer Ingelheim (NCT04111458 and NCT04975256) , and MRTX0902 from Mirati (NCT05578092), are currently undergoing early stage clinical trials.…”