Fakzynja (defactinib)

Our findings reveal a reciprocal regulatory relationship between FAK and ROR1, with both proteins enriched in CLL cells that have exited the lymph nodes. Given defactinib's favorable safety profile in solid tumor trials, combining FAK inhibition with BTK inhibitors could enhance therapeutic efficacy by limiting leukemic clone adaptability and addressing resistance and relapse. While anti-ROR1 therapies showed limited efficacy as monotherapy in CLL trials, targeting multiple nodes of this regulatory network may prove more effective.

P1, N=31, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P1/2, N=4, Not yet recruiting, Verastem Inc.

P1, N=3, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=23 --> 3

Notably, combined treatment with lenvatinib and either the ITGA5 inhibitor volociximab or the FAK inhibitor defactinib effectively reversed lenvatinib resistance in preclinical models. Furthermore, clinical analyses revealed that elevated expression of RPRD1A and ITGA5 correlates with poor response to lenvatinib in HCC patients, reinforcing their potential as predictive biomarkers for therapeutic resistance. Collectively, our results demonstrate that co-targeting the RPRD1A-ITGA5-FAK signaling axis in combination with lenvatinib represents a promising strategy to improve therapeutic efficacy in HCC.

Avutometinib plus defactinib represents a promising targeted therapeutic strategy for recurrent LGSOC, particularly in patients with KRAS-mutant tumors. If confirmed in phase III trials, this combination may establish a molecularly informed disease-specific treatment paradigm with the potential for more durable disease control than existing therapies.

The authors discuss adverse event management and the implications for integration into routine clinical practice. Clinicians caring for patients with low-grade serous ovarian carcinoma can use the drug knowledge and evidence outlined in this review to assist with implementing avutometinib and defactinib therapy.

P2, N=36, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P2, N=50, Recruiting, Emory University | Trial completion date: Sep 2028 --> Sep 2029 | Trial primary completion date: Mar 2028 --> Mar 2029

Notably, these findings were recapitulated through pharmacological inhibition of FAK signaling using Defactinib, an FAK-specific inhibitor. Taken together, our findings reveal that bone-marrow ssDNA may represent a bone microenvironment factor that captures and promotes PCa homing to bone, further suggesting a potential therapeutic strategy for mitigating bone metastasis.

In this study, we identified defactinib, a specific inhibitor of FAK as a novel ferroptosis suppressors...Notably, elevated FAK/SRC-JNK signaling sensitizes cancer cells to ferroptosis-inducing therapies, while inhibition of the FAK/SRC-JNK signaling pathway protects against acute pancreatitis by suppressing ferroptosis. These findings highlight the central role of FAK/ SRC-JNK signaling in controlling ferroptotic cell death and underscore the therapeutic potential of targeting FAK/ SRC-JNK mediated ferroptosis, offering new avenues for the treatment of cancer and acute pancreatitis.