Critical individual roles of the BCR and FGFR1 kinase domains in BCR‐FGFR1‐driven stem cell leukemia/lymphoma syndrome

Abstract

Constitutive activation of FGFR1, as a result of diverse chromosome translocations, is the hallmark of stem cell leukemia/lymphoma syndrome. The BCR‐FGFR1 variant is unique in that the BCR component contributes a serine–threonine kinase (STK) to the N‐terminal end of the chimeric FGFR1 kinase. We have deleted the STK domain and mutated the critical Y177 residue and demonstrate that the transforming activity of these mutated genes is reduced compared to the BCR‐FGFR1 parental kinase. In addition, we demonstrate that deletion of the FGFR1 tyrosine kinase domain abrogates transforming ability, which is not compensated for by BCR STK activity. Unbiased screening for proteins that are inactivated as a result of loss of the BCR STK identified activated S6 kinase and SHP2 kinase. Genetic and pharmacological inhibition of SHP2 function in SCLL cells expressing BCR‐FGFR1 in vitro leads to reduced viability and increased apoptosis. In vivo treatment of SCLL in mice with SHP099 leads to suppression of leukemogenesis, supporting an important role for SHP2 in FGFR1‐driven leukemogenesis. In combination with the BGJ398 FGFR1 inhibitor, cell viability in vitro is further suppressed and acts synergistically with SHP099 in vivo suggesting a potential combined targeted therapy option in this subtype of SCLL disease.

SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

“…These results suggest that blockage of SHP2 and T790M EGFR could potentially serve as a promising dual targeting strategy in LUAD. A few studies have actually shown that SHP2 inhibitors can synergistically promote the killing effect of several targeted drugs through overcoming the drug resistance [ 60 – 62 ]. For example, SHP2 inhibitors could reverse the sorafenib resistance of hepatocellular carcinoma by inhibiting MEK/ERK and AKT signaling [ 62 ].…”

SHP2 inhibition enhances the anticancer effect of Osimertinib in EGFR T790M mutant lung adenocarcinoma by blocking CXCL8 loop mediated stemness

“…Further inhibition of SHP2 (inhibitor and gene knock down) showed a synergistic effect in proliferative suppression of LUAD cells when combined with Osimertinib. Our ndings revealed that blockage of SHP2 and T790M EGFR can be served as a alternative and promising dual targeting strategy in LUAD, actually a bunch of studies have shown that SHP2 inhibitors can synergistically promote the killing effect of several targeted drugs or even overcome the drug resistance [64][65][66]. SHP2 inhibitors can reverse the sorafenib resistance of hepatocellular carcinoma by inhibiting MEK/ERK and AKT signaling [66].…”

Mechanisms of resistance to FGFR1 inhibitors in FGFR1-driven leukemias and lymphomas: implications for optimized treatment

“…Rearrangements involving the BCR gene, however, are more frequently associated with B-lymphomas [ 12 , 14 , 23 ] . While there has been extensive characterization of the function of the chimeric kinases in vitro [ 24 – 26 ] , the common observation is the involvement of constitutive activation of FGFR1 leading to downstream activation of a variety of signaling pathways, although it has been proposed that the fusion partner can possibly influence the phenotypic outcome and survival characteristics from studies in animal models [ 27 ] .…”

“…Dimerization of the chimeric kinases in MLN-eo FGFR1 results in phospho-activation of FGFR1 and targeting the ATP binding site in the kinase has become the prime mechanism of suppressing FGFR1 activation, which is essential for transformation [ 27 ] . Activation of FGFR1 is presumed to phosphoactivate oncogenic downstream protein targets.…”

“…BCR-FGFR1 is unique amongst the various chimeric kinases in that it has dual kinase activity, with a serine-threonine kinase (STK) provided by the BCR component of the chimeric kinase, which activates SHP2 kinase amongst other targets [ 27 ] . Targeting SHP2 with the SHP099 pharmacological agent [ 74 , 75 ] , which stabilizes SHP2 in an inactive conformation, reduced cell proliferation in vitro and leukemogenesis in vivo and, when combined with the BGJ398 FGFR1 inhibitor, showed synergistic effects in vivo [ 27 ] . When other MLN-eo FGFR1 cells expressing other chimeric kinases were treated with SHP099, the effects were less dramatic since they do not have STK activity.…”