Combating CLL Drug Resistance

Challenges remain in Chronic Lymphocytic Leukemia (CLL) treatment as drug resistance ultimately gives rise to tumor relapse especially in high risk CLL cohorts.

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Where do CLL B-cells receive needed nurturing and revitalization?

Of all tissue sites the most likely candidates are the bone marrow (BM) and lymph node however the BM has received the most attention. The leukemic B-cell has been shown to circulate in and out of the BM where it derives critical survival signals from bone marrow stromal cells (BMSCs) and perhaps even more importantly to the patient the BM is able to harbor residual leukemic B-cells giving it time to develop resistance mechanisms that protect the leukemic cell from previously effective therapies.  We have shown that BMSC can protect leukemic B-cells from spontaneous and drug-induced apoptosis(1). But the role of the CLL microenvironment in mediating disease progression and drug resistance while recognized is incomplete. Our report in the Blood Cancer Journal (BCJ) now provides new leads in previously unknown resistant mechanisms utilized by the BM resident leukemic B-cell.

What is the progress in understanding drug resistance based on our report in BCJ?

Previously we have shown that AXL receptor tyrosine kinase is over-expressed and activated in CLL B-cells(2, 3). Our current findings in BCJ demonstrate significantly increased expression of AXL at mRNA and protein levels and β-catenin at the protein level in primary CLL B-cells co-cultured with BMSCs.  This elevation of AXL or β-catenin level in CLL B-cells requires direct contact of CLL B-cells with BMSCs and this increase of AXL and β-catenin is augmented with exposure of BMSCs cultured CLL B-cells to sub-lethal doses of not only chemotherapeutic but also targeted agents including ibrutinib, venetoclax, and TP-0903. The mechanism for altered expression of both AXL and β-catenin in co-cultured CLL B-cells is at least reliant on activation of ERK-42/44 and c-Jun. Moreover, inhibition of ERK activation in co-cultured CLL B-cells inhibited both AXL and β-catenin expression and was accompanied by enhanced CLL B-cell drug sensitivity. 

CLL therapy has shown remarkable improvements in recent years. These have been achieved by penetrating insights into the biology of CLL B-cell signal pathways, which have supported the development of novel drugs. However, the improvements in overall response rates (ORR) and progression free survival (PFS) are muted by the eventual development of resistance to novel agents, intolerance and increasing rates of relapse over time. While drug resistance and relapse is related in part to certain genetic alterations in CLL B-cells, our work in BCJ reminds us that we need to consider the contribution to drug resistance by the microenvironment in CLL. Our earlier findings that targeting AXL by specific AXL inhibitor can robustly generate CLL B-cell apoptosis(2, 4) and the prior observations that AXL and -catenin expression associate with chemoresistance and tumor spread in solid tumors and hematologic malignancies(5-7) has led us to the hypothesis that AXL and/ or -catenin play important hitherto unknown roles in CLL B-cell survival and drug resistance. Our challenge now is to probe via further studies exploiting this novel information on AXL in CLL B-cells to generate effective therapeutic strategies for CLL patients.

REFERENCES

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Dr. Sutapa Sinha

Principal Research Technologist, Mayo Clinic, Rochester MN