When Bcl-2 Is Absent, Anti-IGF1R Antibody Is Effective

Rhabdomyosarcoma's development depends upon an increased IGF1R expression that enhances AKT- and Bcl-xL-mediated cell survival.  If the cancer lacks Bcl-2, an anti-IGF1R antibody  blocks both the receptor and the Bcl-xL-mediated survival signal, and pushes the cell toward self-destruction by apoptosis.

Rhabdomyosarcoma's development depends upon an increased IGF1R expression that enhances AKT- and Bcl-xL-mediated cell survival. If the cancer lacks Bcl-2, an anti-IGF1R antibody blocks both the receptor and the Bcl-xL-mediated survival signal, and pushes the cell toward self-destruction by apoptosis.

A number of new agents being developed to treat cancer are able to kill cancer cells and cause tumor regression, but the mechanisms by which these drugs act, and the biological processes by which they induce cancer cell death are not clear. Understanding which pathways and proteins are influenced by an agent may help predict tumor responses and refine treatment regimens.

Insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs and the IGF-1 receptor (IGF1R) have important roles in growth, development, stress response, aging, and cancer. The IGF1R offers a survival or proliferation advantage in many systems including cancer cells. IGF1R is a target for the development of cancer therapeutics. There are many agents that inhibit IGF1R in clinical development. Some cause rapid tumor regression in selected sarcomas; however, it is not clear by which processes these targeted agents induce cancer cell death.

As reported in a recent issue of Oncogene, Linnia Mayeenuddin, Ph.D., a research fellow working with Liang Cao, Ph.D., in the Genetics Branch, and their colleagues at Center for Cancer Research (CCR) showed that the anti-IGF1R antibody that inactivates the IGF-1 receptor led to rapid cell death and tumor regression in some cases of rhabdomyosarcoma (RMS), which is a cancer of skeletal muscle origin often found in children. A detailed mechanistic analysis revealed that the rapid cell death was operating through cellular components called mitochondria, which are known to play a role in programmed cell death (also known as apoptosis).

The investigators found that the anti-IGF1R antibody induces death in some RMS cells by inhibiting AKT, a protein that blocks apoptosis and aids in cancer cell survival. Further analysis showed that the anti-IGF1R antibody also activates BAD and BAX, which are pro-apoptotic proteins. These two proteins are linked to the AKT signaling pathway and are inhibited by AKT. This promotes cancer cell survival. Interestingly, the anti-IGF1R antibody inhibits an accomplice of AKT—namely, Bcl-xL—that also promotes cancer cell survival. Taken together, these results indicate that the AKT pathway is the primary signaling cascade inhibited by anti-IGF1R antibody. The RMS cells that are not sensitive to anti-IGF1R antibody express a protein called Bcl-2, which is not countered by the antibody. This suggests that only tumors lacking Bcl-2 will be susceptible to anti-IGF1R antibody treatment.

In summary, RMS pathogenesis involves increased IGF1R expression that enhances AKT- and Bcl-xL-mediated cell survival. Inhibition of the IGF1R blocks this survival signal in sensitive cells and makes the anti-IGF1R antibody a plausible treatment for select rhabdomyosarcomas.

Summary Posted: 09/2010

Reference

Oncogene. 2010 Sep 6. [Epub ahead of print] PubMed Link