Jerald P. Radich, MD
Dr. Radich indicated no relevant conflicts of interest.
Sharma SV, Lee DY, Li B, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69-80.
The primary imperative of a cell is to survive. This is fine when the cell is healthy. For a cell transformed into a cancer, this underlying biological drive blocks our ability to bring cures to patients. The cancer cell has many strategies to undermine our treatments, including drug efflux, hiding in protective microenvironment niches, and employing genetic instability to create clones that can emerge during chemotherapy through natural selection. A recent manuscript by Sharma et al. documents another fascinating and frustrating adaptation for drug resistance.
In a very simplistic fashion, one can imagine three varieties of cancer. The first is a homogeneous population of sensitive cells, representing those rare patients for whom chemotherapy works immediately and dramatically. The second type, made up of a homogeneous population of refractory cells, results in early therapeutic failure. The vast majority of cancers are those with a heterogeneous population of both sensitive and resistant cells. Here, therapy is a continual experiment of Darwinian selection, with resistant clones emerging through the selective pressure of the chemotherapy. Sometimes in the setting of relapse, newly emergent clones can be detected by the presence of genetic markers not present in the original sample. Yet, sometimes these cells appear the same as in the original disease. Even more baffling, sometimes retreatment with the original agents will yield a response. How can one explain sensitivity (however brief) in the same cells that were previously resistant?
In this fascinating study, Sharma et al. from Massachusetts General Hospital reported on the phenomenon of reversible, drug-tolerant cells emerging during exposure to chemotherapy agents. The experiments were performed in cell lines, predominately the EGFR mutant non-small cell lung cancer derived cell line, PC9. This cell line is very sensitive to EGFR tyrosine kinase inhibition (TKI). Upon exposure to TKI, a small residual population (< 1 percent) of the original cells persisted with radically ( > 100-fold) reduced sensitivity to the TKI. These “drug-tolerant persisters” (DTPs) could also be found after the PC9 cells were exposed to cisplatin. DTPs were generally quiescent, though ~20 percent resumed normal proliferation in the continued presence of drug, thereby becoming “drug-tolerant expanded persisters” (DTEPs).
Several lines of experiments demonstrated that tolerance was not due to drug efflux or clonal selection of a new mutation. Other key observations in this study were that: 1) PC9 cells plated at low density, even without exposure to drug, occasionally yielded DTP cells, consistent with low-level spontaneous emergence of the resistant phenotype; 2) DTPs and DTEPs, when subsequently grown without drug, would eventually revert back to the sensitive phenotype; 3) mechanistically, the tolerance exhibited by DTPs required the chromatin-remodeling gene histone demethylase KDM5A; treatment of DTPs and DTEPs with histone deacetylase (HDAC) inhibitors caused a reversion back to the drug-sensitive state; 4) formation of DTPs appeared to require IGF-R1 signaling, thus, co-treatment of PC9 cells with a TKI (which would generally permit the emergence of DTPs), and with an IGFR inhibitor and an HDAC inhibitor virtually eliminated the emergence of the drug-tolerant state.
Why is this study important? First, it illuminates a new mechanism of drug tolerance — a transient, fully reversible strategy of the cell to protect itself from a hostile environment (think of a tortoise ducking into its shell, only to emerge when the coast is clear). Second, it suggests that drug intervention to force the cells back down a pathway of drug sensitivity may be possible. Lastly, it may explain why in some cases resistant cells become sensitive again — a potential biological explanation of the phenomenon of the benefit of a drug holiday.
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