Overcoming resistance to oncology targeted therapies though inhibition of downstream signaling pathways: A Chronic Myeloid Leukemia example

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Apr 26, 2017 · 4 min read

By: Dr. Eliza Vakana*


Chronic Myeloid Leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL), two types of hematologic malignancies (blood cancers) are cytogenetically characterized by the presence of the Philadelphia (Ph) chromosome. The Philadelphia chromosome, scientifically known as t(9;22)(q34;q11), is a result of the reciprocal translocation of chromosomes 9 and 22, resulting in the formation of a “novel” chromosome only found in cancer cells and not normal human cells. Chromosomes are made up of DNA, our genetic code, which encodes a number of genes, in humans ~21,000 genes. Through a series of complex processes, proteins, the end products of genes, are synthesized. Despite being an abnormal chromosome, the Philadelphia chromosome also encodes genes, resulting in the formation of protein products. A gene called BCR-ABL is made up of the breakpoint region (BCR) of chromosome 22 and part of the c-ABL (Abelson murine leukemia viral oncogene homolog 1) gene on chromosome 9 (see Figure 1). Its protein product, BCR-ABL, is an example of proteins called oncoproteins, which are proteins whose activity can transform normal cells into cancer cells, leading to the aberrant proliferation of hematopoietic stem cells. Specifically, BCR-ABL is a tyrosine kinase, which is an enzyme that facilitates the addition of a phosphate group on the tyrosine aminoacid of its protein substrates. The classification of the protein as a kinase and the fact that it was only present in cancer cells presented a remarkable opportunity for targeted therapies, as an agent that could inhibit the activity of BCR-ABL would be a possible therapy for these types of blood cancers.

Figure 1: The Philadelphia Chromosome generation t(9;22)(q34;q11). https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=561237

Through many years of effort, in early 2000’s, the medicine imatinib (tradename Gleevec or Glivec) was developed to specifically target the BCR-ABL protein, by binding to the enzymatic pocket that carries out the phosphorylation reaction and inhibiting its activity (see Figure 2). However, even though it is the poster-child for targeted drug discover, some patients develop resistance to this drug through mutations that occur in the BCR-ABL gene and prevent the drug from properly fitting on the enzyme. As a result the patients either stop responding to the drug or might not respond at all from the very beginning in case this specific mutation is present at diagnosis of the disease.

Figure 2: BCR-ABL inhibition with tyrosine kinase inhibitors

The main effort of my doctoral thesis was to try and identify whether novel drug substances or already existing drug substances could be used to inhibit the growth of Ph+ cell lines and Ph+ hematologic cancer patient cells, taking a special interest in the potential inhibition of those resistant to imatinib. In order to do so, my research lab and others had identified that a specific signaling pathway — PI3K/AKT/mTOR — was activated by BCR-ABL and as a result was inhibited by imatinib treatment. My project was directed at examining the effects of inhibition of this pathway using direct, indirect or molecular inhibition. One specific pharmacological inhibitor was an investigational drug substance that directly bound and inhibited mTOR. We identified that it completely inhibited this pathway and resulted in antileukemic effects in both cell lines and patient samples. In fact, this agent was also effective in cells that were resistant to imatinib, concluding that effective inhibition of this pathway could overcome resistance to treatment [1]. The way this agent works is through complete inhibition of mTOR signaling and we provided insight as to why initial mTOR inhibitors had been unable to provide such robust antileukemic effects.

In addition to direct mTOR inhibition, I also examined the effects of indirect inhibition of the pathway, using activators of the protein AMPK that had been found to inhibit mTOR if active [2, 3]. One of the activators that I had used, metformin, is an established anti-diabetic treatment. My research showed that metformin not only inhibited mTOR activity but it also led to the death of CML and Ph+ ALL cancer cells and patient samples1. Furthermore, I inquired whether another molecular inhibition of mTOR could occur, and I identified that the protein SESN3, if properly expressed in BCR-ABL positive cells, could inhibit mTOR pathway signaling and also inhibit growth of BCR-ABL positive leukemia cells [4]. Overall, I identified that both direct pharmacological inhibition, indirect pharmacological inhibition, as well as molecular inhibition of the mTOR pathway inhibit the proliferation of BCR-ABL positive cells.

Our research provided the basis for further development of mTOR inhibitors for use in BCR-ABL positive malignancies and also for further research into the potential repurposing of known drugs, such as metformin, as anti-cancer agents in cancers that have an abnormal activation of mTOR signaling.


References:

[1] Carayol N*, Vakana E*, et al. 2010. PNAS *equal contribution, url: http://www.pnas.org/content/107/28/12469.long

[2] Vakana E, et al. 2011. Blood, url: http://www.bloodjournal.org/content/118/24/6399.long

[3] Vakana E, et al. 2011. Oncotarget, url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282089/

[4] Vakana E, et al. 2013, PLoS One, url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832611/


*Current Position: Regulatory Affairs Associate, Medochemie Ltd

Email: elizavakana@gmail.com

Linkedin: https://www.linkedin.com/in/evakana/

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