On August 26, the FDA approved Rasonque (daraxonrasib), developed by Revolution Medicines. It is the first broad RAS-targeted inhibitor approved for advanced pancreatic cancer, marking a notable milestone for a disease that has historically had very few options. 

For forty years, researchers considered the RAS protein “undruggable” because its surface is so smooth that typical drugs couldn’t find a pocket to latch onto. Yet, RAS-activating mutations drive up to 25% of all human cancers, particularly aggressive ones like pancreatic ductal adenocarcinoma. As a neuroscientist who has also worked in oncology, I’ve followed RAS and its most common subtype: KRAS.

In healthy cells, RAS behaves like a master switch that turns on and off to control cell growth. When mutated or hyperactivated, KRAS stays in the “on” position, leading to unchecked tumor growth. While targeted drugs for specific KRAS mutations representing 10-15% of KRAS cancers have emerged in recent years, Rasonque broadly locks the activation site of multiple RAS subtypes, and regardless of mutations.

Doubling Survival

In its Phase 3 study, Rasonque doubled the median survival time for patients with metastatic pancreatic cancer who had relapsed or seen their tumors grow after standard chemotherapy. Survival extended to 13.2 months compared to 6.7 months for standard care. Given this difficult, late-stage disease, this result represents a major advance. The FDA approved the drug after a swift one-month review.

Like many cancer drugs, Rasonque can cause burdensome side effects, including severe skin rashes and mouth sores, but it was rare, more serious risks that initially restricted the trial to late-stage patients. An ongoing trial is now exploring whether Rasonque can be used earlier, as a post-resection adjuvant therapy to prevent metastasis.

The Filamin A Connection

My interest in RAS comes from simufilam, a small molecule that binds the scaffolding protein filamin A. Originally developed for Alzheimer’s disease, it is soon to enter clinical trials for tuberous sclerosis complex (TSC) epilepsy. 

We examined simufilam in cancer cell lines and mouse models because we showed that filamin A in Alzheimer’s brain and Alzheimer’s mice was phosphorylated at S2152, and simufilam reduced it. Because this phosphorylation state of filamin A was well known to occur in cancer, we wondered if simufilam might have potential to treat cancer. 

In vitro tests across pancreatic, glioblastoma, melanoma, breast, and small cell lung cancer cell lines showed that simufilam reduced the proliferation markers PCNA and Ki67. It also reduced the activation of mTOR—a notorious cancer driver that sits directly downstream of KRAS and is hyperactivated by it. Interestingly, simufilam reduced the activation of KRAS itself in two different pancreatic cancer cell lines (MiaPaCa2, which carries a KRAS mutation, and BxpC3, which does not). In mouse models, simufilam successfully shrank tumors formed by both pancreatic lines.

Protein interactions hold the clue to this mechanism. In cancer cells, filamin A binds directly to KRAS, keeping the pathway active. This filamin A is misshapen and phosphorylated at S2152. By restoring filamin A back to its normal shape and reducing the S2152 phosphorylation, simufilam reduces filamin A’s abnormal linkage to KRAS, slowing down KRAS activation. 

Interestingly, in healthy cells, filamin A connects to Ras-GAP instead—which is a negative regulator that helps turn RAS “off.” This filamin A – Ras-GAP interaction is restored in cancer cells treated with simufilam. While simufilam has not been tested in cancer, the biology is compelling.

“Undruggable” Becomes Druggable

The approval of Rasonque reminds us that “undruggable” targets are sometimes just waiting for the right structural biology strategy or a new point of intervention. Whether directly targeting the activation site of these proteins or targeting regulating proteins such as filamin A, the toolkit for treating difficult cancers is steadily expanding. 

Today, we can celebrate the addition of a broad RAS inhibitor for patients navigating a pancreatic cancer diagnosis.