Doxorubicin and etoposide are both broad chemotherapeutics that disrupt cell division. They have both been in use for decades and are given as a treatment for several types of cancer, among which breast cancer, leukemia and lung cancer. Worldwide hundreds of thousands of patients have benefited from these drugs. But in some patients their effect is insufficient, or they don't work at all. Therefore, cancer researchers are trying to unravel what can make cancer cells insensitive to these drugs. This is an important step towards 'personalized medicine', in which patients only receive drugs that work against their specific tumor, and don't receive drugs that are ineffective for them but do have (serious) side effects.
Independent mechanisms
One resistance mechanism against doxorubicin and etoposide is already known (the 'drug pump' MDR1). But often this isn't the explanation for observed insensitivity against the drugs. So there must be other resistance mechanisms. Prof. dr. Sjaak Neefjes of the NKI and his team have now found three new, independent resistance mechanisms. His work was published 'Online First' in the journal Cancer Research on August 10. The first authors of the study are PhD-student Ruud Wijdeven and postdoc Baoxu Pang.
DNA double-strand breaks
Doxorubicin and etoposide disrupt cell division by generating DNA double strand breaks during the division process. Due to these breaks, cells can't function properly, causing them to die. Cancer cells are more sensitive for this disruption mechanism than normal cells because of their unusually high division rate. The three newly discovered resistance mechanisms all revolve around proteins or protein complexes that relate to DNA double strand break processes. If the protein Keap1 or the protein complex SWI/SNF don't function properly, there will be less DNA breaks, causing the cancer cells to survive. And if the protein C9orf82 doesn't function, the cancer cells are better able to repair the breaks. In these ways, cancer cells can evade the effect of doxorubicin and etoposide. Neefjes and his team discovered these new resistance mechanisms using several types of tissue, among which a large databank of breast tumor tissue.
Relevance
Neefjes: "What makes this discovery very relevant, is that we know mutations in these three proteins are quite common in cancer patients." It is known that, for instance, 12 to 15 percent of the lung cancer patients harbor mutations in their tumors that disable the protein Keap1. And the protein complex SWI/SNF is dysfunctional in as much as twenty percent of all human tumors. This means that this discovery might help to better predict which drugs will be beneficial for quite a large number of patients. Neefjes: "If you know in advance that a patient has a mutation in one of these proteins, you know that it is very likely that treatment with doxorubicin or etoposide won't work. So in these instances you may want to give another type of drug. And as we have shown in our laboratory, such alternatives exist."
Predictive value
Cancer patients will not benefit immediately from this new discovery. Neefjes' study was performed retrospectively, with tumor tissue of patients whose treatment outcome was known. To be sure that the discovered mutations also have predictive value, a so-called prospective study is required. First, it is necessary to determine what the best alternative treatments are for patients with (possible) resistance against doxorubicin and etoposide. Next, it needs to be determined whether treatment with these alternative drugs based on the presence of the mutations does indeed lead to better treatment outcomes compared to the standard treatment.