The interplay between microenvironmental signaling and novel targeted drugs in CLL

Despite the rapid expansion of novel treatment options, chronic lymphocytic leukemia (CLL) remains an incurable disease. Development of drug resistance is strongly influenced by the leukemic microenvironment within the lymph nodes and spleen. Within these microenvironments, CLL cells interact with non-leukemic accessory cells that provide the necessary external signals and induce multiple downstream signaling pathways that drive survival, proliferation and drug resistance of CLL cells. With the goal of developing novel therapeutic strategies to overcome development of drug resistance, the signaling pathways that lead to adhesion, proliferation, DNA-repair and inhibition of cell death were dissected.
We found that targeting multiple phosphoinositide 3-kinase (PI3K) isoforms not only prevents adhesion and proliferation but also induces cell death. Moreover, dual inhibition of DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) results in cell death, inhibition of proliferation and drug resistance. Finally, we demonstrated that the survival of the CLL cells in the microenvironment critically depends on the anti-apoptotic protein Bcl-XL. These data provide biological rational of combining non-chemotherapeutic agents with different modes of action to avoid drug resistance.