Cancer Cells Push a Notorious Oncogene Onto Their Surface, Creating a New Drug Target

For fifty years, the SRC enzyme has been one of oncology's most famous molecules - and one of its most frustrating targets. Identified at UCSF in the 1970s by J. Michael Bishop and Harold Varmus as the first oncogene (earning them the 1989 Nobel Prize), SRC was known to drive tumor growth from inside cells. Drugs designed to block it had to penetrate the cell membrane, and once inside, they could not distinguish cancer cells from healthy ones. The therapies did not work well.

Now, researchers at the same university have found that SRC is not hiding inside cancer cells after all. It is sitting right on the surface, exposed and targetable - a finding that could open SRC to an entirely different class of therapies.

How cellular garbage pushes SRC outside

The discovery, published in Science, came from the lab of Jim Wells, PhD, professor of Pharmaceutical Chemistry at UCSF. First author Corleone Delaveris, PhD, tracked SRC's journey within cancer cells grown in the lab and found the enzyme getting caught up in the cell's waste disposal system.

Normal cells trap waste in small membrane-bound sacs called lysosomes, which break down and recycle cellular debris. But cancer cells divide furiously, producing more waste than their recycling machinery can handle. When the system overloads, these sacs fuse with the outer cell membrane and dump their contents outside. SRC gets swept along in this process, ending up on the cell's exterior surface.

The key finding: SRC was present on the surface of bladder tumor cells taken from patients at UCSF, but not on healthy bladder tissue or on immune cells. This specificity is critical - it means antibody-based therapies could potentially target SRC on tumors without attacking healthy tissue.

Two antibody approaches shrank tumors in mice

The team tested two strategies. In collaboration with UCSF professor of Radiology Michael Evans, PhD, they aimed experimental radioactive antibodies at surface SRC in mice implanted with human tumor cells. The radioactive payloads accumulated in the cancer cells. They also engineered antibodies designed to recruit the patient's own immune cells to recognize and kill SRC-positive cancer cells. Both approaches reduced tumors in the mouse models.

The researchers found SRC on the surface of bladder, colorectal, breast, and pancreatic tumor cells, and they estimate the target could apply to up to half of all tumors. UCSF has licensed the antibodies and related molecules to Inversion Therapeutics, a company co-founded by Wells, Evans, and Delaveris, to explore their therapeutic potential.

From impossible target to accessible flag

The SRC story illustrates how assumptions can constrain therapeutic development for decades. Because SRC was an intracellular protein, researchers spent years designing small molecules that could cross cell membranes to reach it. Those drugs were limited by their inability to distinguish cancerous from healthy cells, leading to unacceptable side effects.

Surface-exposed SRC changes the therapeutic equation entirely. Antibody drugs - which are large molecules that cannot enter cells - become viable. And because SRC appears on tumor surfaces but not on healthy tissue (at least in the tumor types tested), the targeting could be far more precise than previous approaches.

The mechanism that pushes SRC to the surface - lysosomal overload and membrane fusion - is a general feature of aggressive cancers, not specific to one tumor type. This suggests the approach could have broad applicability, though that hypothesis needs validation across more cancer types.

What remains preclinical

All the therapeutic results so far come from mouse models implanted with human tumor cells. These xenograft models are useful for proof-of-concept but do not fully replicate the complexity of human cancer, including the tumor microenvironment, immune system interactions, and drug metabolism.

The specificity of surface SRC for tumor cells over healthy tissue was demonstrated in bladder cancer patient samples, but similar validation has not been published for other cancer types. The estimate that up to half of all tumors might express surface SRC is based on what is known about SRC overexpression and lysosomal dysfunction in cancers broadly - not on direct surface measurements across tumor types.

The antibody therapies are experimental. Moving from mouse models to human clinical trials typically takes years and involves significant hurdles in manufacturing, dosing, safety testing, and regulatory approval. The licensing deal with Inversion Therapeutics is a first step, not a timeline for patient access.

There is also a basic biological question: do cancer cells with surface SRC develop resistance by reducing SRC expression or by restoring their lysosomal recycling capacity? If tumors can adapt to hide SRC again, the therapeutic window could be narrower than hoped.

But after fifty years of trying to hit SRC from the inside, finding it on the outside represents a genuine shift in what is possible.