Integrins and drug resistance in small cell lung cancer
Abstracts
Initial Award Abstract |
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Small cell lung cancer constitutes about 20% of all lung cancers. This form of cancer is characterized by early and widespread metastases, which makes the treatment of the disease difficult. Most patients with small cell lung cancer initially respond to chemotherapy, but small cell lung cancer almost invariably relapses and becomes resistant to chemotherapeutic treatment. Therefore, the patient 2-year survival rate remains less than 5%. The reasons why small cell lung cancer is especially resistant to chemotherapy are not clear. Most chemotherapy drugs are thought to work so that they activate self-destructive mechanisms in cancer cells and these cells therefore "commit suicide" in response to chemotherapy. It has been hypothesized that resistant cancer cells somehow refuse to commit suicide in response to chemotherapeutic drugs. Our work supported by TRDRP has demonstrated that certain molecules that are on the cell surface, known as integrins, block suicide signals in cancer cells. Normally, the role of integrins is to anchor cells in their place within a tissue. It is thought that in cancer cells, integrins have lost their normal function and instead, they may aid the movement and metastasis of cancer cells. Our original hypothesis was that integrins could also be crucial for the development of drug resistance, and we have been able to show that this is indeed the case, at least in cell culture models. Thus, ligation of certain integrins, but not others, protects cancer cells against chemotherapeutic drug-induced suicide. Importantly, we have been able to diminish this protective effect by inhibitory anti-integrin antibodies in cell culture models. We have also made advances in understanding the mechanisms by which integrins instruct the cancer cells not to commit suicide. Specifically, we have identified an intracellular molecule named PI 3-kinase as a crucial mediator of survival signaling downstream of integrins. Additional data suggest that integrins activate the PI 3-kinase pathway by activating the tyrosine kinase activity of the EGF receptor in cancer cells. This finding demonstrates a new cross-talk between integrins and growth factor receptors during cancer progression, and is especially important taken into consideration the currently ongoing clinical trials in lung cancer with EGFR inhibitors such as Tarceva and Iressa. Our long-term objective is to test whether preventing integrin and/or PI 3-kinase function in a mouse cancer model will increase the effectiveness of chemotherapeutic treatment. If these studies prove to be successful, our findings may provide a considerable benefit in the therapy of small cell lung cancer. |
