Gab2 signaling in chronic myeloid leukemia cells confers resistance to multiple Bcr-Abl inhibitors

Abstract

Grb2-associated binder 2 (Gab2) serves as a critical amplifier in the signaling network of Bcr-Abl, the driver of chronic myeloid leukemia (CML). Despite the success of tyrosine kinase inhibitors (TKIs) in CML treatment, TKI resistance, caused by mutations in Bcr-Abl or aberrant activity of its network partners, remains a clinical problem. Using inducible expression and knockdown systems, we analyzed the role of Gab2 in Bcr-Abl signaling in human CML cells, especially with respect to TKI sensitivity. We show for the first time that Gab2 signaling protects CML cells from various Bcr-Abl inhibitors (imatinib, nilotinib, dasatinib and GNF-2), whereas Gab2 knockdown or haploinsufficiency leads to increased TKI sensitivity. We dissected the underlying molecular mechanism using various Gab2 mutants and kinase inhibitors and identified the Shp2/Ras/ERK and the PI3K/AKT/mTOR axes as the two critical signaling pathways. Gab2-mediated TKI resistance was associated with persistent phosphorylation of Gab2 Y452, a PI3K recruitment site, and consistent with this finding, the protective effect of Gab2 was completely abolished by the combination of dasatinib with the dual PI3K/mTOR inhibitor NVP-BEZ235. The identification of Gab2 as a novel modulator of TKI sensitivity in CML suggests that Gab2 could be exploited as a biomarker and therapeutic target in TKI-resistant disease.

Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia

“…7 However, based on experiences with other targeted therapy compounds such as imatinib or vemurafenib in CML 44 and melanoma, 42,45 respectively, it will be important to identify additional targets to identify synthetic lethal combinations by targeting 2 or more signaling hubs that are critical for tumor growth and survival, and to efficiently counteract the development of therapy resistance. Here, we report for the first time the functional significance and surface overexpression of the IGF1R protein and its baseline phosphorylation in human CLL cells ( Figure 1B).…”

BCR-ABL inactivates cytosolic PTEN through Casein Kinase II mediated tail phosphorylation

“…On the contrary, it is well demonstrated that BCR-ABL transformation requires PI3K-AKT signaling. [15][16][17][18][19][20][21][22][23][24][25] Furthermore, it was also shown that PIP3 levels are dramatically increased in CML. 26 Therefore, we hypothesized that PTEN could be functionally inactivated in the cytoplasm of CML cells.…”

Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1

“…In parallel, another study investigated the role of GAB2 overexpression in conferring resistance of CML cells to ABL1 TKIs and found that GAB2-mediated TKI resistance is also dependent on its interaction with SHP2 and p85. 50 Analysis of GAB2-dependent signals in BCR-ABL1-expressing primary myeloid and B-lymphoid cells revealed distinct roles for the GAB2 SHP2 and p85 binding sites in BCR-ABL1-induced transformation. In agreement with our previous observations, 16 AKT [53][54][55] We also discriminated the roles of SHP2 and PI3K binding to GAB2 in BCR-ABL1 signaling; whereas SHP2 binding is required for activation of ERK, S6, and STAT5, PI3K binding is required only for AKT activation.…”