Cancer vs. Targeted Agents: A Molecular Arms Race

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Mia Hubert

Chronic myelogenous leukemia (CML) is a slow-progressing disease resulting from an overproduction of blood cells originating from the bone marrow, known as myeloid cells. Before 2001, the standard of care included chemotherapy and bone marrow transplantation (BMT). Unfortunately, chemotherapeutic approaches were non-curative and BMT entailed a high-risk procedure with potential long-term complications. As a result, the 5-year survival of CML patients was estimated to be around 30-40%.

The discovery of the major genetic fusion event involved in most adult CML cases as well as the advent of targeted molecular medicine transformed the landscape for CML treatment.  In the 1970’s, a reciprocal fusion event between chromosomes 9 and 22—resulting in what is termed the Philadelphia chromosome—was found to be a key genetic event in CML cells. A decade later, this chromosomal aberration was found to fuse the Bcr and Abl genes, resulting in an overactive kinase (an enzyme that phosphorylates other proteins). This kinase activity drives the transformation of immature blood cells into cancerous cells and promotes tumor cell survival. 

Understanding the underlying molecular pathology of CML ultimately resulted in the FDA approval of imatinib (Gleevec) in 2001. Gleevec specifically inhibited the activity of the BCR-ABL tyrosine kinase, making it the first targeted molecular therapy against cancer. Gleevec was regarded as a breakthrough in CML treatment: patients showed exceptional response rates, with 5-year survival rates upwards of 89%.

While tyrosine kinase inhibitors (TKIs) like Gleevec revolutionized CML treatment and the world of targeted molecular therapies, they are not immune to the age-old biological phenomena of adaptation and evolution. Certain traits in animals provide a selective advantage in stressful environments. Bacteria can develop resistance to antibiotics used to treat infection. In the case of TKIs, the BCR-ABL fusion kinase can develop mutations that confer resistance to Gleevec, resulting in non-response to the drug. These BCR-ABL-dependent mutations often reduce imatinib binding affinity or efficacy. In fact, 50% of CML patients develop resistance to Gleevec, the most common being the T315I substitution mutation⁶.

Second- and third-generation TKIs were approved in the USA in 2006 and 2012, respectively, to tackle the issue of TKI resistance. As expected, however, additional modes of resistance have occurred, including BCR-ABL-independent mechanisms such as increased drug efflux or metabolism. Unfortunately for patients, sequential treatment failures with TKIs are often an indicator of poor response to other TKIs. As a result, CML’s BCR-ABL and TKIs have been engaged in an “evolutionary arms race”: science develops a new way to target this cancer’s weaknesses, while CML “responds” by developing novel methods of resistance. And the cycle repeats.

Unfortunately, patients that fail to respond to first- and second-line TKI treatments often do not benefit from a third-line TKI treatment. Furthermore, TKIs must be taken daily and indefinitely, but adherence is difficult due to some severe side effects such as fatigue, depression, nausea and digestive issues. As a result, some current efforts are aimed at alternative therapies due to TKI resistance or discontinuation. Some focus has shifted to third-generation TKIs effective against most BCR-ABL mutants with improved safety profiles, such as olverembatinib, vodobatinib, and asciminib. 

As the main driver of CML oncogenesis, most ‘alternative’ therapies continue to focus on BCR-ABL with TKIs, but in combination with other anticancer drugs to increase efficacy and reduce resistance. These include small molecule inhibitors targeting other proteins or pathways that are aberrantly upregulated in CML. Interestingly, immunotherapy via immune checkpoint inhibitor (ICI) treatment—which has found success in treating cancers such as melanoma and lung cancers—is beginning to find a place in CML therapy. Ongoing trials are investigating the ICIs nivolumab and avelumab in combination with TKIs in CML patients⁸.

Despite the continuing difficulties in CML treatment, there is no doubt that Gleevec dramatically improved the outlook for CML patients and paved the way for other treatments targeting molecular drivers in cancer. As we further our understanding of the underlying molecular activity behind cancer cell growth and spread, targeted therapy via small molecule drugs has become increasingly popular and useful in the clinic. 

Edited by Keighley Reisenauer

References

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