The Pill That Could · A Different Cancer

A Different Cancer, part 2

But tamoxifen was, in 1986, the only such drug. The other two-thirds of breast cancers — the ones without the estrogen receptor, called ER-negative — were treated with the cytotoxic regimens that had been more or less the same for fifteen years. There was no targeted option for them, because there was no known target.

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Dennis Slamon was, in 1986, in his late thirties, an early-career physician-scientist at UCLA. He had trained as an oncologist; he had also trained, on the molecular biology side, in the school of thought that the next generation of cancer drugs would come from understanding cancer at the level of specific genes and specific proteins. He was, by training, well placed to look at breast cancer through the lens of molecular biology rather than the lens of clinical oncology.

What he had been thinking about, since his postdoctoral years, was the question we have already met in chapter three: oncogenes, proto-oncogenes, the Bishop-Varmus discovery that cancer-causing genes were normal cellular genes gone wrong. The list of cellular oncogenes had grown rapidly through the early 1980s. Most of them were on the list because they had been found as the cancer-causing element of some retrovirus and then traced back to a normal cellular gene. ABL, from chapter three, was one of these. So was MYC, fingered in some of the lymphomas. So was RAS, which would turn out to be the most common single oncogene in human cancer.

And so, by the early 1980s, was a gene called neu — named, by the laboratory of Robert Weinberg at MIT, after the rat neuroglioblastoma cells in which it had first been identified. Weinberg's group had isolated neu by a clever piece of experimental detective work: they had taken DNA from rat tumor cells, transferred it into normal cells in a dish, and watched which fragments of tumor DNA could turn the normal cells cancerous. The fragment that did so contained the neu gene. The protein the gene made was a receptor on the cell surface, related to but not identical with another receptor called the epidermal growth factor receptor. The relationship was close enough that the human equivalent of neu was eventually given a name in the same family: HER2 — the second of three closely related receptors, with HER1 being the EGF receptor itself and HER3 being a third member of the family that was identified later.

Weinberg's neu had been identified through its capacity to cause cancer in laboratory cells. Slamon's question, beginning around 1984, was whether the human gene was doing anything in the actual cancers people got. He needed to find out whether HER2, in human breast tumors, was altered — mutated, amplified, overexpressed, however — in a way that might matter clinically.

He started building the tissue bank.

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It is worth pausing on what amplification means, because it is the molecular event the rest of this chapter rests on.

A normal human cell has two copies of every gene that isn't on a sex chromosome. The two copies are on the two homologous chromosomes — one inherited from each parent. If a cell needs more of a particular protein, it normally turns on the existing copies more vigorously, transcribing more RNA from them, translating more protein from each copy of RNA. The number of copies of the gene itself, in the DNA, stays the same.

Sometimes, however, the number of copies changes. A region of a chromosome can be duplicated — copied, intact, so that the same stretch of DNA appears twice in a row. The duplication can itself be duplicated. The duplications can iterate, sometimes producing a region of chromosome that contains many tandem copies of what used to be a single gene. The cell, with extra copies of the gene, can make more of the corresponding RNA and more of the corresponding protein, simply through having more templates to read.

This is, in normal cells, an unusual event. In cancer cells, it is more common. The genetic instability of cancer cells — the kind of instability that produces translocations, mutations, deletions, and duplications at higher rates than in healthy cells — produces gene amplifications too. And when an oncogene happens to fall in a region that gets amplified, the amplification can drive the cancer. The cell ends up with twenty, fifty, a hundred copies of a gene whose protein product, at normal levels, mildly encourages growth and, at radically elevated levels, drives uncontrolled growth.

HER2, when amplified, was doing something like this. The receptor was a transmembrane protein — a protein with one part outside the cell, one part embedded in the cell membrane, and one part inside the cell. The outside part bound a ligand, a small signaling molecule. (HER2's specific ligand was, for a long time, mysterious; we now know it pairs with other HER family members rather than binding a dedicated ligand of its own.) The binding caused the receptor to dimerize — to pair up with another receptor in the membrane — and the dimerization activated the inside part, which was a tyrosine kinase. The kinase, once activated, phosphorylated targets inside the cell, setting off the same general kinds of pathways BCR-ABL was setting off in CML cells: pathways that drove proliferation, suppressed cell death, and changed the cell's behavior toward its surroundings.

When HER2 was present at normal levels, this signaling happened only when the cell received the right ligand at the right time. When HER2 was amplified — with fifty copies of the receptor on the cell surface instead of two — the dimerization could happen more or less continuously, just from the sheer density of receptors bumping into each other in the membrane. The cell was getting a constant signal to grow, similar in spirit to what BCR-ABL was doing in CML, although through a different molecular route. The receptor wasn't mutated. There was just too much of it.

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