Early-stage clinical data from our company and others point to the Wnt/β-catenin pathway as a new avenue for targeting multiple cancer types.
For more than four decades, the “big four” oncology targets—KRAS, MYC, TP53, and Wnt/β-catenin —have represented a holy grail for cancer drug development. Each plays a critical role in tumor biology and is implicated across a broad range of cancers, yet all four were long considered out of reach for different reasons.
At the ASCO 2026 annual meeting earlier this year, KRAS was emphatically crossed off that list when Revolution Medicines presented Phase 3 data showing that daraxonrasib, now on the market as Rasonque, nearly doubled survival compared with chemotherapy in patients with metastatic pancreatic ductal adenocarcinoma. A target once dismissed as impossible to drug now has approved medicines, late-stage clinical programs and billions of dollars in investment behind it. The KRAS story is a reminder that progress begins with deeper understanding of target biology and the perseverance to translate that understanding into therapeutic reality.
The next target to be removed from this “out of reach” list may well be Wnt/β-catenin, which is dysregulated in roughly a third of all cancers. While no drugs targeting this pathway have yet reached the approval stage, promising early- and mid-stage clinical results from Iterion Therapeutics, where I serve as CEO, as well as from Parabilis Medicines and Sapience Therapeutics, point to a new way of throwing a wrench in the gears of certain cancers.
How Wnt/β-catenin became druggable
As a founder, scientist and executive in multiple venture-backed companies that have pursued previously undrugged targets, I was drawn to Wnt/β-catenin as one of oncology’s most important and challenging pathways. In healthy tissues, it helps coordinate tissue maintenance, stem cell renewal and repair. When activated in tumors, however, the pathway can promote growth, stemness, immune evasion and therapeutic resistance. Wnt/β-catenin is implicated in colorectal, hepatocellular, gastric and endometrial cancers, and is often associated with more aggressive tumor behavior.
One challenge is that β-catenin is not a typical enzyme with well-defined, druggable pockets. Its oncogenic activity depends on large, flat protein-protein interfaces and transcriptional complexes that are inherently difficult to target. β-catenin also has essential roles in normal tissue homeostasis and cell-cell adhesion, meaning that broad pathway inhibition can cause unacceptable toxicities. Indeed, this was a major limitation in early Wnt/β-catenin programs, which underestimated the complexity of Wnt biology.
Then the industry realized that drugging the undruggable requires a different approach. KRAS became druggable when researchers identified vulnerabilities created by specific cancer-causing mutations, enabling the development of drugs that selectively target mutant KRAS proteins and better identification of the patients most likely to benefit. First-generation inhibitors of the cancer-associated KRAS G12C mutation proved the target could be reached. More recent RAS programs have expanded the field from this single allele toward broader therapeutic applications. A recent analysis of the Rasonque Phase 3 data show that certain mutational subgroups fared better than others, suggesting there is still significant opportunity to improve outcomes for patients with KRAS-mutated tumors.
A similar evolution is now underway for Wnt/β-catenin. A small group of companies is targeting Wnt’s activation of transcriptional machinery in cancer cells, while aiming to avoid the toxicities historically associated with broader upstream Wnt inhibition. At Iterion, we are pursuing this strategy by targeting TBL1, a nuclear regulator of β-catenin–mediated transcription with a defined binding pocket that is not involved in essential β-catenin functions in healthy cells. Our small molecule asset tegavivint is designed to disrupt the TBL1:β-catenin interaction, resulting in degradation of nuclear β-catenin and the inhibition of oncogenic gene expression.
Other companies are pursuing complementary approaches. Parabilis Medicines’ zolucatetide targets the β-catenin:TCF interaction using its Helicon peptide platform, while Sapience Therapeutics is developing ST316, a peptide directed at the β-catenin:BCL9 interface.
Early clinical data support the concept that Wnt/β-catenin transcriptional activity can be targeted in humans without eliciting toxicity. At ASCO 2026, Iterion reported encouraging Phase 1 data with tegavivint in heavily pre-treated patients with hepatocellular carcinoma (HCC) that contains Wnt-pathway activating mutations, including excellent tolerability, monotherapy clinical responses and evidence of pathway inhibition. While still early, these data provide the first clinical evidence that a Wnt/β-catenin–directed therapy can deliver meaningful benefit in a biomarker-selected HCC population.
Parabilis, meanwhile, reported early monotherapy activity with zolucatetide in desmoid tumors, a rare Wnt/β-catenin–driven sarcoma, including compelling responses and disease control. And Sapience recently presented encouraging early Phase 2 data with ST316 in second-line colorectal cancer in combination with standard therapy. Together, these data are promoting Wnt/β-catenin from a theoretical pathway of interest to a clinically relevant cancer target.
The future of Wnt/β-catenin
It is becoming clear that Wnt/β-catenin is no longer undruggable. A deeper understanding of biology has opened a new door, and we think the next several years will determine just how many new cancer treatments we can find as we walk through it.
Science alone is not sufficient for successful drug development. It must be matched by capital, conviction and a willingness to test difficult hypotheses in patients. Parabilis’ recent record-breaking IPO, supported in part by enthusiasm around zolucatetide clinical data, shows that investors are willing to commit meaningful capital to companies pursuing historically difficult intracellular oncology targets.
At Iterion, we are now evaluating tegavivint as a monotherapy and in combination with Exelixis’ next-generation multi-kinase inhibitor zanzalintinib in second- and third-line Wnt-mutated HCC. Additional clinical programs in colorectal cancer and pediatric osteosarcoma are also actively enrolling. Wnt-directed agents may ultimately be most powerful as part of rational combinations matched to tumor biology. As evidence, Iterion recently announced encouraging Phase 1b clinical data evaluating the combination of osimertinib and tegavivint in patients with first-line EGFR-mutated NSCLC. If the tolerability is maintained in larger studies, it could lead to further exploration of Wnt-directed therapies across a broader range of cancers and combinations, both to enhance established treatment modalities and reduce or eliminate therapeutic resistance.
The field must still identify which tumors are truly Wnt-dependent, which mechanisms produce the best therapeutic window and which combinations generate the most meaningful benefit for patients. From that vantage point, Wnt/β-catenin looks less like an impossible target and more like the next major test of whether oncology can again make the undruggable druggable.
