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Research Summary

Past and Current Research Summary

1) Acquired resistance to EGFR inhibitors in NSCLC:

During my postdoctoral training in Dr. Daniel Tenen’s laboratory at Beth Israel Deaconess Medical Center, we discovered that acquired resistance to EGFR TKIs can be caused by a secondary mutation of the EGFR gene, leading to a T790M amino acid change in the EGFR tyrosine kinase domain1. In addition, we were able to identify a class of irreversible EGFR inhibitors that can successfully overcome such resistance2. Based on our observation, some irreversible EGFR inhibitors have entered clinical trials. We also identified and characterized EGFR exon 20 insertion mutations, whose sensitivity to EGFR TKIs is determined by its association with the TKIs3. Therefore, a novel strategy to overcome primary and acquired resistance to tyrosine kinase inhibitors is sorely needed. To identify downstream targets of EGFR inhibition, we conducted transcriptional profiling study and identified cyclin D1 as one of the most down-regulated genes upon EGFR treatment in cells harboring EGFR mutants4. Furthermore, given that cyclin D1 is one of the Wnt/β-catenin pathway’s targets, we demonstrated that β-catenin plays a major role in lung cancer development induced by EGFR mutations5.

2) The role of Bim in tyrosine kinase inhibitor-induced apoptosis:

To better understand the mechanisms involved in the apoptotic pathway in EGFR-mutant NSCLC, we have identified a key mediator of tyrosine kinase inhibitor-induced apoptosis, the “BH3-only” protein Bim6. Our results demonstrate that the sensitivity of cell lines to EGFR inhibitors was determined by the up-regulation of Bim and that the T790M secondary mutation was able to overcome this up-regulation and inhibit apoptosis6. We propose that activation of Bim may be a shared mechanism by which tumor cells driven by “oncogenic addiction” undergo apoptosis7. In this context, it is possible that enhancement of Bim expression or activation of its down-stream targets may be a promising strategy for the treatment of EGFR-mutant NSCLC, particularly in the context of mutations conferring secondary resistance to TKIs. In addition, we extended this observation to hematopoietic diseases, and found that Bim is critical in JAK2 inhbition-induced apoptosis in myeloproliferative neoplasms as well7.

3) CARM1 plays an important role in proper control of proliferation and differentiation of pulmonary epithelial cells:

My laboratory has demonstrated that the lungs of newborn mice lacking Carm1 have substantially reduced airspace compared to their wild type littermates. In the absence of Carm1, alveolar type II cells show increased proliferation as measured by Ki-67 staining. In addition, lungs from mice lacking Carm1 have immature alveolar type II cells and an absence of alveolar type 1 cells. Gene expression analysis revealed dysregulation of cell cycle genes and markers of differentiation in the Carm1 knockout lung8. Our findings suggest that CARM1 is required for proper control of proliferation and differentiation of the airway epithelium.

Future Research

1) The role of the Bcl-2 family proteins which are responsible for TKI-induced apoptosis:

The overall goals of this project are to identify precise mechanism(s) by which TKIs induce apoptosis and to investigate a better strategy to treat cancers induced by oncogenic kinases such as mutant EGFR or JAK2. Based on our preliminary results described above, we will focus on the possibility that enhancement of Bim expression or activation of its down-stream targets may be a promising strategy to treat lung cancers or MPNs induced by mutant EGFR or JAK2, respectively.

2) The role of Wnt/β-catenin signaling in pathogenesis of lung cancer driven by oncogenic kinases:

The overall goals of this project are to characterize Wnt/β-catenin signaling as the mechanisms of acquired resistance to TKI therapy in lung cancer and to explore the possibility that inhibition of this pathway could be a novel therapeutic strategy.

3) The mechsnisms by which EGFR-T790M memerges:

T790M (a threonine to methionine amino acid alteration) is detected in more than 50% of gefitinib/erlotinib-resistant patients. Cytosine (C) to thymine (T) single base pair change leads to T790M in the ATP-binding pocket of the EGFR. However, the precise mechanism of emergence of this mutation is not clear. We will investigate the molecular mechanims how T790M is generated by EGFR TKIs.