Targeting ROR1 May Offer a Way Around Resistance in MCL

A small molecule inhibitor of ROR1, a receptor largely absent from normal adult tissue but overexpressed in mantle cell lymphoma (MCL), eliminated both treatment-naive and drug-resistant MCL cells in preclinical models, and resistant cell lines could not be established against it even after prolonged exposure, authors from Sweden have reported in new findings.¹

Results from the team, based at Karolinska Institutet and Linköping University, were published in the journal Blood Neoplasia.¹ Their paper identifies KAN571C as a small molecule that consistently shut down phosphorylation of ROR1 and its downstream signaling in MCL cells that become resistant to both ibrutinib (Imbruvica; Janssen), a first-generation Bruton tyrosine kinase (BTK) inhibitor, and venetoclax (Venclexta; Genentech/AbbVie), until recently the only BCL2-inhibitor on the market.

According to the authors, this suggests that once MCL cells become resistant to both BTK and BCL2, they lean on ROR1 to stay alive. “Our observations imply that ROR1-associated signaling may serve as an adaptive mechanism to sustain cell viability during drug treatment, underscoring the potential of ROR1 inhibition as a tentative strategy in overcoming resistance in MCL,” they write.¹

Resistance Is a Major Challenge in MCL

MCL remains an aggressive, largely incurable non-Hodgkin lymphoma that is diagnosed in between 4000 and 6000 patients per year in the United States, according to the National Cancer Institute.² The authors write that even with newer standards of care, including ibrutinib-based chemoimmunotherapy up front and the combination of ibrutinib-venetoclax in relapsed disease, resistance typically emerges at some point.

“Like with most lymphomas, most of the patients with MCL initially respond to treatment but frequently experience relapse because of the emergence of drug resistance,” they write. “Around one-third of patients with MCL are resistant to [ibrutinib] or other BTK [inhibitor].”¹

Ibrutinib resistance, they write, is often traced to BTK mutations or activation of alternative survival pathways such as PI3K/AKT, while venetoclax resistance has been linked to upregulation of antiapoptotic proteins like MCL-1 and BCL-XL. Patients who become refractory to both drug classes—known as double resistance—have few remaining options, making new targets a priority in MCL and in related B-cell malignancies such as chronic lymphocytic leukemia (CLL).

ROR1, a pseudokinase involved in noncanonical Wnt5a signaling, has drawn interest as a target precisely because of this restricted normal-tissue expression paired with overexpression in several cancers. This research team for this paper had previously shown that KAN571C could induce apoptosis in ROR1-positive MCL and CLL cells, including ibrutinib-resistant CLL cells.³ This new study extends that work specifically to double-refractory MCL models.¹

What the Study Data Showed

Using JEKO-1, Granta-519, and Z138 MCL cell lines, the investigators built ibrutinib-resistant, venetoclax-resistant, and double-resistant models through continuous, escalating drug exposure. KAN571C produced dose-dependent cytotoxicity in both naive and resistant models across all 3 cell lines. The small molecule’s effect was most pronounced in venetoclax- and double-resistant JEKO-1 and Granta-519 cells, where KAN571C's cytotoxicity significantly exceeded that seen in naive cells.

Mechanistically, KAN571C dephosphorylated ROR1 at its tyrosine kinase and proline-rich domains in resistant cells—changes that were not seen, or were far less pronounced, in naive cells. This was accompanied by downregulation of PI3K/AKT and β-catenin signaling and by activation of caspase-dependent apoptosis, evidenced by cleavage of caspase 3 and PARP. Venetoclax- and double-resistant Granta-519 cells, notably, were the only Granta-519 models in which KAN571C triggered this apoptotic cleavage, aligning with the high cytotoxicity observed in those groups.

Of note, no KAN571C-resistant cell lines could be generated, even after 2 weeks of continuous exposure—a notable contrast to the relatively fast resistance that developed against ibrutinib and venetoclax alone.

The authors also identified a compensatory relationship between ROR1 and BTK signaling. KAN571C treatment increased BTK phosphorylation across resistance models.

“This compensatory relationship is also supported by our previous study, in which similar trends were reported in patient samples after ROR1 inhibition,” they wrote, noting that this may point to combination strategies down the line.¹

Limitations and Next Steps

The findings are confined to in vitro cell line models, which do not capture the tumor microenvironment, immune interactions, or pharmacokinetic factors that shape real-world drug response. The authors note that freshly obtained MCL cells are difficult to culture long-term, which is why the resistance models were built from established cell lines rather than patient samples. They call for xenograft and patient-derived model validation, along with more detailed pharmacological characterization of KAN571C—including pharmacokinetics, target engagement, and selectivity—before the compound could be considered for clinical development.

Still, the inability to generate KAN571C-resistant cell lines despite repeated attempts stands out as a signal of durability that the authors say supports continued investigation of ROR1 as a therapeutic target in MCL and, potentially, other B-cell malignancies where double refractoriness remains a persistent clinical challenge.

References

1. Zhong W, Hojjat-Farsangi M, Barde S, et al. Targeting ROR1 with KAN571C disrupts resistance networks in mantle cell lymphoma. Blood Neoplasia. 2026;3(4):100269.
2. National Cancer Institute. Mantle Cell Lymphoma Treatment (PDQ®)–Health Professional Version. Accessed September 12, 2026. https://www.cancer.gov/types/lymphoma/hp/mantle-cell-lymphoma-treatment
3. Ghaderi A, Zhong W, Okhovat MA, et al. A ROR1 small molecule inhibitor (KAN0441571C) induced significant apoptosis of mantle cell lymphoma (MCL) cells. Pharmaceutics. 2022; 14(10):2238. doi:10.3390/pharmaceutics14102238