Experimental Calithera compound cripples key lung cancer mutations

Micrograph of small cell lung cancer
Lung cancer cells with KRAS and KEAP1 mutations are vulnerable to a drug that prevents them from using energy to promote growth.

Calithera Biosciences’ experimental cancer compound CB-839 works by inhibiting glutaminase, an enzyme that promotes the survival of some types of cancer cells through the production of the amino acid glutamate. The company is conducting a phase 1 trial in several solid tumor types, including non-small cell lung cancer (NSCLC).

Now, scientists at New York University’s Perlmutter Cancer Center have discovered that two commonly mutated genes in lung cancer may make some tumor cells especially vulnerable to CB-839’s mechanism of action. They believe their findings could lead to more precise patient targeting in the ongoing clinical trials—and not just in lung cancer.

The researchers found that a mutated gene called KEAP1 teams up with another abnormal gene, KRAS, to cause lung cancer cells to grow aggressively. In so doing, they expel one type of glutamate and break down another to make energy. When the scientists tested CB-839 in mouse models of lung adenocarcinomas that had both mutations, the drug stopped the tumor growth.

The reason, the researchers discovered, was that the KEAP1-mutated cells used up all the glutamate to make antioxidants needed to keep the cancer cells alive. But then there wasn’t enough glutamate left to fuel the cancer growth normally driven by KRAS. So the cancer cells starved. They published their findings in the journal Nature Medicine.

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The NYU team used the gene-editing system CRISPR-CAS9 to create a realistic model of dual-mutated adenocarcinoma cells in a matter of months. Then they screened multiple drugs until they hit upon CB-839.

Lung cancers that possess KRAS and KEAP1 mutations account for about 10% of diagnosed cases, estimates Thales Papagiannakopoulos, a co-author of the study and assistant pathology professor at NYU School of Medicine. That’s about 9,000 patients per year. But the scientists believe their findings may prove the usefulness of glutaminase inhibitors beyond lung cancer. That’s because KEAP1 mutations are also found in melanoma, bone cancer, kidney cancer, urinary tract cancer and colon cancer, they explained in a second study in the journal eLife.

Papagiannakopoulos says he has approached Calithera about investigating whether CB-839 is most effective in lung cancer patients with KRAS and KEAP1 mutations. Meanwhile, his team plans to work on studying 16 other commonly mutated genes in lung cancer, in the hopes of identifying other vulnerabilities that might be able to be addressed with drugs.