Tumors find many ways to evade groundbreaking cancer drug - Science Magazine

Patients with lung cancer (shown here) developed a wide array of resistance mechanisms to a KRAS inhibitor drug.

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.

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 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.

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.

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.