Researchers were ecstatic 2 years ago when, after decades of effort, they devised drugs that could block a tumor-promoting protein in cancer patients called KRAS, which previously seemed impervious to treatment. But many of these KRAS inhibitors—the first of which was approved by U.S. regulators in May—quickly lost their luster, like other targeted cancer drugs: Most patients’ tumors resumed growing after a few months, as their cancer cells became resistant to the inhibitors. Now, a study finds that the roots of this resistance are surprisingly complex, with tumors using an array of escape routes to evade the attack on KRAS.
“There appears to be huge variation” in drug resistance mechanisms, says lung cancer specialist Colin Lindsay of the University of Manchester, who was not involved in the study.
Up to 20% of tumors carry mutations in the gene for KRAS, a protein that sets off a cascade of signals within a cell that causes it to divide. In normal cells, this pathway stays off most of the time, but in cancers in which the gene is mutated, it stays on, causing cells to divide uncontrollably.
The mutant KRAS protein in these cancers was long considered “undruggable,” partly because the protein’s surface is smooth, and thus has no pockets to which a drug can bind. But in 2013, chemical biologist Kevan Shokat of the University of California, San Francisco, found a small molecule that slipped perfectly into a groove of KRAS proteins that had a cancer-promoting mutation called G12C. In clinical trials, a drug similar to the molecule shrank tumors in many lung cancer patients for about 7 months before resistant cells emerged—and the cancer returned.
To find out how the cancer cells counter such drugs, Dana-Farber Cancer Institute medical oncologists Andrew Aguirre and Mark Awad and colleagues analyzed tissue samples from 38 lung and colon cancer patients in a clinical trial for a KRAS inhibitor called adagrasib, made by the biotech company Mirati Therapeutics. The researchers sequenced the genes of tumor tissue and tumor DNA circulating in the blood, both at the start of drug treatment and after tumors regrew, looking for any differences that could explain the newfound resistance. They found genetic alterations or other changes in 17 patients’ tumors that appeared to explain resistance to the drug.
Seven patients’ tumors had changes in the KRAS gene itself. Most also had alterations in other genes in the KRAS cell division signaling pathway, and in two cases, tumors apparently became resistant by undergoing more profound, nongenetic changes that turned the tumor into a different type of lung cancer based on how it looked under a microscope. Seven of 17 patients had at least two potential resistance-conferring genetic changes in their tumors, the researchers report today in The New England Journal of Medicine.
This array of resistance mechanisms sets KRAS inhibitors apart from two approved, widely used drugs that target proteins called EGFR and ALK, which drive the growth of some lung cancer patients’ tumors. When these tumors develop resistance, the patient often turns out to have one of just a few common resistant mutations in their cancer cells. That has led companies to develop next-generation drugs that either target that mutation or several mutations at once; these have kept some patients’ tumors in check for years.
Aguirre says the complexity of KRAS resistance mechanisms suggests researchers may need to try several different drug combinations to overcome the problem—some of these are already in trials, he notes.
Shokat says one silver lining is that tumors that developed resistance to KRAS inhibitors usually didn’t lose the G12C mutation, which would have taken away the pocket where a drug can bind. “The most feared resistance mechanism doesn’t seem to be as easy to evolve” as it is for some other targeted drugs, he says. And despite the challenges, Lindsay is optimistic: “I doubt the research community will be daunted by this … given how far they have come over nearly 40 years.”
sciencemag.org, 23 June 2021