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Cell Signaling Problem Set

Problem 12: Cancer Therapy

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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?

A. Inhibiting signaling pathways can benefit people with cancer.
B. Rapidly dividing cancer cells that have lost checkpoint systems insuring genome fidelity can develop resistance to specific anti-cancer drugs.
C. 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 patient survival.
D. All of the above.


Cancer therapy

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 BCR-ABL kinase.
  • 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.
Problem 12 | Answer

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