Photo by National Cancer Institute on Unsplash
The fight against cancer is a fight against a living thing, with its own intelligence. Our bodies are smarter than our minds by whatever metric you might pick. Each cell regulates the expression of thousands of genes simultaneously, while many of us get flustered trying to text and use the ATM at the same time. From the scale of the tissue to the scale of the single cell, innumerable processes are orchestrated for the best possible outcome: the propagation and maintenance of life.
Cancer cells retain all that intelligence, but add their own perverted missionary twist. Cancers are smart individually and diverse as a group, such that cancer is thought of not as one disease, but an overwhelming array of disparate malignancies. Each tumor in each patient is unique, hence the challenge and allure of personalized medicine.
But even this fact undersells the complexity, and ignores a key dimension: the progression of an individual tumor over time. Tumors do not just grow monolithically, but evolve as they swell. They recruit blood vessels to feed their burgeoning populations. They also respond strategically to the drugs meant to kill them.
Resistance to chemotherapeutics is common, deadly, and poorly understood. New research from the UCSF lab of Dr. Steven Altschuler and Dr. Lani Wu, published on February 19th in Nature Communications, has begun to shed light on the diverse number of mechanisms that a single cancer cell can use to acquire drug resistance.
The research acknowledges cancer’s frightening protean power, and moves towards our own evolution of more effective treatment strategies to combat resistance mechanisms. As in chess, it is essential to think many moves ahead.
Chemotherapeutic resistance can be classified into two camps: intrinsic resistance and acquired resistance. Intrinsic resistance exists before drug treatment even starts. Since cancer cells are a heterogeneous mix, and can acquire mutations more rapidly than normal cells, it is possible that some cells are already predisposed to be resistant to a drug.
Acquired resistance, on the other hand, represents a more shifty undertaking on the part of the tumor, a conscious movement, like moving a king out of check. The molecular tools that cells use to acquire resistance are not well known, but many experiments point to a “persister state,” in which cells seem to hunker down for a period of weeks, not dying from the chemotherapy but not growing either.
Eventually, some of the cells that have existed in this dormant state emerge with the ability to divide. It was this transition, from persisting cells to expanding cells, that Altschuler and Wu were interested in exploring. The research was led by co-first authors Michael Ramirez, Satwik Rajaram, and Robert Steininger.
To model the transition from persister to expander, they established a “clonal” cell line from a patient with non-small cell lung cancer (NSCLC). In a clonal cell line, all cells that grow out are derived from a single originating cell. They did this to ensure that all cells in their experiment were close to genetically identical, helping them focus on acquired resistance instead of intrinsic resistance.
There are a myriad of molecular re-wirings that may make a cell cancerous. The cells used in this study - PC9 cells - divide like crazy because of signals coming from a cell surface protein called EGFR. EGFR, like many proteins that are mutated or overproduced in cancer cells, has been studied and targeted with specific drugs.
Erlotinib is an example of one such drug, marketed in the U.S. by Genentech. It is a little molecule that fits into a pocket of EGFR, preventing it from transmitting a pro-proliferative signal to other proteins. Many chemotherapeutics work like this: little monkey wrenches that disrupt molecular machinery. This recent study exposed PC9 cells to erlotinib, creating a subset of cells newly resistant to the drug.
While erlotinib may disrupt EGFR signaling, there are many possible workarounds for cancer cells. They may emerge with mutated EGFR, creating slightly different versions of the protein with pockets that no longer fit the drug. They may simply create more EGFR. But they also may use another signaling protein entirely. Cellular signaling pathways are traffic webs beyond our ability to entirely understand, model, or block. Shutting down the BART does not block access to the East Bay – it forces commuters to find alternative solutions.
To see what kind of alternative pathways the persister-derived cells were using, the researchers used two complementary methods. First, they exposed the cells to other drugs known to target other specific pathways. Second, they sequenced the genomes of the cells to find which genetic changes had occurred.
The take-home discovery: resistance mechanisms are messy. Among 17 cases of acquired resistance, they found huge variability in the genetic changes these resistant cells had acquired and the drugs that they were vulnerable to.
As the authors noted in the paper, “this heterogeneity presents considerable clinical challenges for ‘personalized’ therapy.”
Better understanding of the persister state – how do cells get chosen as persisters? are persisters initially different or all the same? – should help us follow how acquired resistance fans out in so many molecular directions.
To anticipate your opponent’s move, you must first know how they think. Cancer, like a chess grandmaster, is both smart and unpredictable.
