VS-4718

Treatment of ESCC cells with the FAK inhibitor PND-1186 reduced MFAP2, induced the activation of the FAK-AKT pathway in vitro, and suppressed lung metastasis in a mouse model of ESCC. These findings support a major role for MFAP2 in promoting ESCC metastasis, in part via the activation of FAK-AKT signaling, and highlight the potential of MFAP2 as a promising therapeutic target for ESCC.

Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.

Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.

Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).

In vitro, cell viability and proliferation assays were used to test abemaciclib (CDK4/6 inhibitor), defactinib (FAK inhibitor) and VS-6766 (RAF/MEK inhibitor) as monotherapy and in combination...The efficacy of VS-4718 (in vivo formulation of defactinib) and abemaciclib were evaluated in a subcutaneous IOMM-lee meningioma model (having CDKN2A loss) in nude mice... Abemaciclib showed promising efficacy in preclinical meningioma xenografts with CDKN2A loss. Studies to evaluate these therapies in other orthotopic models are underway.

Furthermore, inhibition of FAK activity by VS-4718, the FAK inhibitor, enhanced antitumor effect of GDC-0449, the HH inhibitor, both in xenografted models and in vitro assays. Clinically, CCL22/Gli1 axis is used to evaluate ESCC prognosis. Overall, our study establishes the communication of FAK with HH pathway and offers the novel mechanism related to Gli1 activation independent of Smoothened as well as the rationale for the anti-ESCC combination treatment.

VS-4718 is a focal adhesion kinase (FAK) inhibitor that has shown synergistic anti-tumor activity with avutometinib in other cancer models, as it blocks the potential of FAK to function as an adaptive resistance mechanism to RAF/MEK inhibition. Combination of avutometinib with FAK inhibition showed improved in vivo preclinical anti-tumor efficacy relative to either agent alone in an LGSC PDX model with wildtype KRAS and with a RAF1 mutation. These data support an ongoing registration-directed study with avutometinib ± the FAK inhibitor defactinib for patients with recurrent LGSC (NCT04625270).

This effect was more pronounced for FAK (PND-1186) small molecule inhibitor treatment; consistent with previously published data. Additionally, our study showed no evidence of a correlation between the mRNA expression of inhibitor of apoptosis (IAP) gene family members and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in the MPM cell lines and correlated with poor sensitivity to YM155.

PND1186, FAK inhibitor, inhibits breast cancer metastasis induced by IGSF9 knockdown in vitro and in vivo. Taken together, IGSF9 is trans-activated by p53 and inhibits breast cancer metastasis by modulating FAK/AKT signaling pathway. IGSF9 could serve as a prognostic marker and potential therapeutic target for breast cancer.

The FAK inhibitor VS-4718 reversed the metastasis mediated by EXOC4 overexpression and suppressed the tumor growth of patient-derived xenografts derived from DGC with high EXOC4 expression. The EXOC4-FAK axis could be a potential therapeutic target for patients with DGC with high expression of EXOC4. The EXOC4-FAK axis promoted DGC metastasis and could be a potential therapeutic target for patients with DGC.

Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.

Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

We showed that MPM cells with high CDH1 mRNA levels exhibited resistance to the FAK inhibitor PND-1186...A protein-protein interaction study showed that EGFR is linked to the FAK pathway, and a target scan of the microRNAs revealed that microRNAs (miR-17, miR221, miR-222, miR137, and miR148) interact with EGFR 3'UTR. Transfection of MPM cells with these microRNAs sensitised the CHD1-expressing FAK-inhibitor-resistant MPM cells to the FAK inhibitor.

We previously reported that FAK inhibition by the selective inhibitor VS-4718 exerted anti-leukemia activities in AML. The combination also markedly extended survival of a second PDX model developed from an aggressive, p53-mutated complex karyotype AML sample. The data suggest that the combined inhibition of FAK and BCL-2 enhances anti-leukemia activity in AML at least in part by suppressing MCL-1 and BCL-XL and that this combination may be effective in AML with p53 and other mutations, and thus benefit high-risk AML patients.

Indeed, MEK-ERK pathway inhibition by multiple approved MEKis (e.g., trametinib), combined with FAK inhibition (VS-4718 or defactinib), showed remarkable synergistic growth inhibitory effects in UM cells. By coupling the unique genetic landscape of UM with the power of unbiased computational pipelines and systems biology genetic screens, our studies revealed that FAK and MEK-ERK co-targeting may provide a new network-based precision therapeutic strategy for mUM treatment. Indeed, the combination of defactinib and RO5126766 is currently being evaluated in patients with various solid tumors (NCT03875820), and could be explored in mUM based on these preclinical findings.