Cancer’s notorious resistance to therapy is often explained as the result of natural selection of newly mutating cells. Cancer-killing drugs wipe out nearly all of a tumor’s cells, but random mutations may allow for drug resistance in some cells, and these survivors go on to harm or kill patients. But some researchers now suggest an alternate, controversial theory for how this resistance develops — cancer-killing drugs trigger resistance in the very cells they were supposed to kill, a concept presented and reviewed May 12 in the British Journal of Cancer.
Genome sequencing of tumor cells has suggested that random mutations and natural selection can lead to drug resistance. However, the review authors, cancer biologists Angela Pisco and Sui Huang at the Institute for Systems Biology in Seattle, note that prior research also found that some cancer cells inevitably survive cancer-killing drugs, even when they’re not armed with drug-resistance mutations.
Instead, they note that a single human genome can generate a multitude of distinct cell types, or phenotypes, even without any alterations to their genomes. This property, called “phenotypic plasticity,” can lead cells to even switch phenotypes, which can be passed, some suggest, to subsequent generations.
Pisco and Huang note multiple studies that have found phenotypic plasticity in cancer. They conclude that anti-cancer drugs may stress cancer cells, pushing them into activating networks of genes resembling those in stem cells, undifferentiated cells with potential to give rise to multiple cell types.
Stem cells are often resistant to toxins and resilient to DNA damage. Hence some researchers hypothesize that cancer-killing drugs push cancer cells into acquiring stemness, making them more resilient and resistant to therapies.
Alternatively, some portion of cancer cells may naturally possess a drug-resistant stem-like phenotype. Anti-cancer drugs may then simply kill off cancer cells that are not stem-like, allowing their genetically identical drug-resistant siblings to proliferate.
It’s a controversial notion, but could potentially explain what many researchers and clinicians have observed. “It’s pretty clear that some cancer cells are inherently resistant to therapy not because they acquired mutations,” says neurosurgeon and cancer biologist Eric Holland, director of the human biology division at Fred Hutchinson Cancer Research Center in Seattle. “If you look at heterogeneity in a tumor, then the cells that are resistant do not necessarily have genetic alterations that explain their resistance. What makes them different are phenotypic things such as expression of stem cell markers, or their location in tumors.”
One way to help confirm or refute this new theory would be to monitor how cancer cells that survive therapy become stem-like, Huang says. Such experiments would need to monitor these cells before and after therapy, and at single-cell resolution over time.
If drug resistance is a cellular response to potentially lethal stresses, one could in principle inhibit this response with drugs. Such drugs are already known to exist, and “could be given to patients prior or concomitantly to chemotherapy,” Huang says, adding that it may also be possible to modify current therapies so that they circumvent stress responses. Oncologists could, for example, prescribe smaller and more frequent doses of such drugs. Other studies might investigate whether milder therapies could render cancers inert without triggering stress responses, a potentially less toxic approach for patients. (For more on novel cancer therapy approaches, see this recent PNAS Opinion piece.)