Harvard Expert Sees Potential in BCL-2 Combos

Jane De Lartigue, PhD
Published: Sunday, May 27, 2018
Dr Anthony Letai

Anthony Letai, MD, PhD
The prospect of developing anticancer strategies that target the apoptotic pathway most likely lies in combinations involving members of the B-cell lymphoma-2 (BCL-2) protein family, according to Anthony G. Letai, MD, PhD, a leading investigator in the field.

, Letai discussed the complex nature of apoptosis and efforts to target the process.

OncLive: How does apoptosis fit into the hallmarks of cancer?

Letai: Both the older and newer constructs of Hanahan and Weinberg’s “Hallmarks of Cancer” list “resisting cell death” as a hallmark. The concept is that a lot of the bad things cancers do, such as overexpress oncogenes, invade and metastasize out of their native locations, and proliferate relentlessly, should provoke apoptotic signaling (apoptosis is a prominent form of programmed cell death) that should kill the cancer cells. The fact that some cancer cells escape this level of control suggests that they have selected for evasion of programmed cell death. Indeed, many mouse genetic models of impaired apoptosis display accelerated oncogenesis, supporting programmed cell death as 1 level of control of cancer.

Cancer cells may select for blocks in apoptosis that enable it to escape endogenous death signaling induced by oncogenesis, but there is no mechanism for them to foresee future exposure to chemotherapy and select for the extra apoptotic blocking that resistance to these agents would require. This often results in cancer cells that survive, but just barely. Of course, this principle exists on a broad spectrum, with leukemias and other blood cancers being the most primed for apoptosis, in concert with their broad chemosensitivity. Many solid tumors, however, exhibit more profound blocking, which yields less chemosensitivity.

What is the role of MCL-1 in that hallmark ability?

MCL-1 is one of the proteins of the BCL-2 family that regulate apoptosis. It is a so-called antiapoptotic protein, as it opposes commitment to apoptotic cell death by binding and sequestering proapoptotic proteins. Theoretically—and demonstrated in mouse models—high levels of MCL-1 expression can facilitate tumorigenesis. In human tumors, amplification of the MCL-1 locus is one of the more common somatic genetic abnormalities.
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