The Biology Project
Cell Signaling > Problem
12: Cancer Therapy
Tutorial to help answer the question
A new drug, STI-571 or Gleevec, specifically inhibits the Abl tyrosine
kinase that is mutated in chronic myeloid leukemia. Treating patients
with the drug dramatically improves survival, but people with a "blast
crisis" form of the cancer begin to develop resistance. Which of
the following statements are important conclusions from studies on the
use of STI-571 in cancer treatment?
Problem 12 |
||Inhibiting signaling pathways can benefit people with cancer.
||Rapidly dividing cancer cells that have lost checkpoint
systems insuring genome fidelity can develop resistance to specific
||Acquisition of resistance to STI-571 shows that the
same specific enzyme changes occur, suggesting that developing new
drugs that target mutations leading to resistance may further improve
||All of the above.
Cell signaling systems are particularly important in cancer. The disease
results from genetic changes in cells that frequently alter signaling
systems and pathways.
Inhibiting the BCR-ABL tyrosine kinase in chronic
myeloid leukemia (CML)
Reference: New England Journal of Medicine 344, 1084 (2001).
- CML results from cells that undergo rapid proliferation. The cancer is
always accompanied by a genetic translocation between chromosomes
9 and 22, producing an activated tyrosine kinase called BCR-ABL.
- Brian Druker, a scientist at Oregon University, discovered an inhibitor
called STI-571 (Gleevec) that blocks the BCR-ABL tyrosine kinase.
The inhibitor design was possible because the complete structure of
the ATP binding site was known.
- Treating patients with CML who had failed all other standard
therapies showed a high percentage with tumor regression including complete remissions.
- In one study, 53 out of 54 cancer patients showed complete lasting responses.
- The inhibitor also inhibits another kinase (C-kit) that is important in metastatic gastrointestinal stromal tumor, and a
recent study (New England Journal of Medicine 344, 1052 (2001)) showed metastataic tumor regression in a cancer that had
previously been considered to be untreatable and always fatal.
Patients who relapse
- Patients in the early or chronic stage of CML show complete lasting responses
(53/54 in one study).
- In later stages, the disease enters a blast-crisis and frequently shows loss of p53, an important tumor
suppressor that helps prevent chromosomal errors.
Treating with STI-571 reduces tumor load, but
many of the patients relapse.
Why does STI-571 sometimes fail?
- Reference: Science 293, 876 (2001)- Replacement of threonine by isoleucine in BCR-ABL
retains kinase activity but eliminates binding by STI-571.
- Most relapsing patients had this single mutation.
- These results imply that designing a new drug that can block the mutant
- This represents targeted therapy, directed against the mutation(s) that
lead to a cancer cell phenotype. This should both be safer and much more
effective than current therapies.
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