STAT+: The race to catch KRAS, pancreatic cancer’s ‘greasy ball,’ and create the most promising drug in decades

Leanna Stokes had gotten into the habit of asking her oncologist what might be next for her treatment, and for good reason. Stokes, a 36-year-old gymnastics manager from New Rochelle, New York, had received one of the most difficult diagnoses in oncology: metastatic pancreatic cancer.

Her oncologist kept mentioning two syllables, KAY-ras, referring to her cancer’s mutation on the KRAS gene. Mutations in this gene can make cancers more aggressive.

But for Stokes, it was a possible key to extending her life. “She always mentioned this — KRAS, KRAS, KRAS,” Stokes said of her oncologist.

As Stokes proceeded to receive line after line of chemotherapy, she would remind herself, “It’s there. It’s there.

It’s there. Then finally, it was my turn.” Just a few years ago, such a refrain might have sounded odd to pancreatic cancer experts.

For most of the nearly 50 years since KRAS was first discovered, scientists struggled to effectively drug the cancer protein. When Kevan Shokat, a biochemist at University of California, San Francisco, finally discovered how to drug a rare subset of KRAS mutant cancers, the first-generation drugs were a clinical disappointment.

For the roughly 1% of pancreatic cancer patients who could receive them, the drugs improved outcomes only marginally, with resistance forming rapidly. “We did not have a home run on the first effort,” said Channing Der, a pancreatic cancer researcher at the University of North Carolina, Chapel Hill.

“It’s fair to say we’ve been disappointed by the durability of the responses.” But once Shokat had shown it could be done at all, more and more companies jumped into developing drugs for KRAS, with new agents now regularly moving into clinical trials. The company leading the field has been Revolution Medicines, with the drug daraxonrasib, which targets KRAS and related proteins.

This was the drug that Stokes got on her clinical trial. It transformed her life, she said, enabling her to live far longer than most patients with her diagnosis.

It’s also generating immense excitement among oncologists and drug developers, who say it heralds a new era for pancreatic cancer medicine and could bring new treatments for other cancer types with KRAS mutations including lung, colorectal, endometrial, and more. Beyond Revolution Medicines, dozens of other companies are also testing promising KRAS inhibitors in the clinic.

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