Each year more than 1.7 million people in the China die of cancer – the major disease group that has seen the least improvement in cure rate in the past decades. Why is cancer so difficult to treat and why do almost all treatments, however new and sophisticated, almost inevitably fail after an initial success in shrinking the primary tumor? The main reason for failure of cancer therapy is the inexorable, often unfathomably rapid development of drug resistance.  It is commonly believed that therapy resistance is the result of a selection during therapy of mutations in cancer cells that happen to render the cells resistant to the cytotoxic attack – in the same way that bacteria develop resistance against antibiotics: a process of Darwinian evolution, driven by random mutations and survival of the fittest (cancer cell)  

However, the latest discovery from the Huang's lab at the Institute for Systems Biology in Seattle now nails down what some have long suspected but did not dare to utter: namely that resistance development does not simply follow the Darwinian mechanism of evolution and that instead cancer cells actively adapt to the external threat. This alternative mechanisms, called  ‘Lamarckian evolution” postulates that traits can be acquired by active adaptation of each individual and passed on to the next generation, thereby contributing to evolution. While outlandish when it comes to the evolution of complex organisms, there is actually, at the level of individual cells, such as bacteria or cancer cells, the no reason why the Lamarckian mechanism process should not occur. After all, normal cells are extremely versatile: they produce the 1000s of distinct cell types in the body without a single mutation of their genome when they respond to external signals during development and they pass on the acquired cell phenotype to their cell progenies. The Huang lab found that besides killing tumor cells as they are designed for, chemotherapy drugs also push the small number of lucky surviving cells into a new cell state: Their entire gene expression program changed, leading to the expression of many proteins that help the cell survive the cytotoxic to change their gene expression to survive better.  For instance, if a leukemia cell faced chemotherapy but did not die (for whatever reason) it turned on the expression of the protein  MDR1  - long known to help cells cope with drugs by immediately ejecting foreign molecules out of the cell.  Researchers in the Huang lab went a long way to show that this change of cell phenotype following drug treatment was truly an adaption at the level of each individual surviving cells, and not the selection of the few mutant cells that were already there and happen to be better at surviving – as postulated by the orthodoxy of Darwinian evolutions.  They also found the molecular pathway through which chemotherapy turned on the MDR1 gene: the “Wnt pathway” an ancient pathway which is normally involved in maintenance of the stem cell states was activated by the chemotherapy agent, and its experimentally blocking it suppressed the activation of the MDR1 gene.

Thus, cancer cells overcome therapy not only because of Darwin’s principle of the  “survival of the fittest” but also with help of another principle, articulated by  Nietzsche: “What does not kill me makes me stronger”.  This mechanism requires an active adaptation of each cell (as opposed to the passive selection) and may present a vulnerability that can targeted by a new generation of anti-drugs.

原文阅读
PiscoBrockHuang2013_NonDarwinianDrugResistance_NatureComm (2).pdf