Focal adhesion kinase plays a dual role in TRAIL resistance and metastatic outgrowth of malignant melanoma

Abstract

Despite remarkable advances in therapeutic interventions, malignant melanoma (MM) remains a life-threating disease. Following high initial response rates to targeted kinase-inhibition metastases quickly acquire resistance and present with enhanced tumor progression and invasion, demanding alternative treatment options. We show 2nd generation hexameric TRAIL-receptor-agonist IZI1551 (IZI) to effectively induce apoptosis in MM cells irrespective of the intrinsic BRAF/NRAS mutation status. Conditioning to the EC50 dose of IZI converted the phenotype of IZI-sensitive parental MM cells into a fast proliferating and invasive, IZI-resistant metastasis. Mechanistically, we identified focal adhesion kinase (FAK) to play a dual role in phenotype-switching. In the cytosol, activated FAK triggers survival pathways in a PI3K- and MAPK-dependent manner. In the nucleus, the FERM domain of FAK prevents activation of wtp53, as being expressed in the majority of MM, and consequently intrinsic apoptosis. Caspase-8-mediated cleavage of FAK as well as FAK knockdown, and pharmacological inhibition, respectively, reverted the metastatic phenotype-switch and restored IZI responsiveness. FAK inhibition also re-sensitized MM cells isolated from patient metastasis that had relapsed from targeted kinase inhibition to cell death, irrespective of the intrinsic BRAF/NRAS mutation status. Hence, FAK-inhibition alone or in combination with 2nd generation TRAIL-receptor agonists may be recommended for treatment of initially resistant and relapsed MM, respectively.

An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines

“…Moreover, simultaneous exposure to the FAK inhibitor CT-707 abolished cabozantinib-induced FAK activation, implying the possible synergistic effect of combination therapy interfering with these two intracellular signaling proteins. Regarding the factor of drug resistance, several reports have proposed FAK and Src as players in therapy resistance in different tumor models [ 70 , 71 , 72 ]. Their downregulation increases the cytotoxicity of docetaxel in ovarian cancer [ 73 ], as well as their sensitivity to gemcitabine in pancreatic cancer [ 74 ].…”

Roles and inhibitors of FAK in cancer: current advances and future directions

“…In the cytoplasm, activated FAK initiates survival pathways in a PI3K and MAPK-dependent manner. Simultaneously, within the nucleus, the FERM domain of FAK hinders the activation of p53, thereby preventing inherent cell apoptosis ( Del et al, 2022 ; Ke et al, 2022 ). Previous studies have delineated various mechanisms through which FAK promotes tumor cell survival and proliferation.…”

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

“…FAK also has a distinct role independent of focal adhesions as a result of a nuclear localisation signal within the FERM domain of the protein ( Aplin et al, 1998 ; Parsons et al, 2000 ). Normally, interrupting focal adhesions through cellular detachment results in rapid dephosphorylation of FAK and its cleavage facilitated by caspase-3, -6 and -9, resulting in translocation to the nucleus where FAK prevents activation of wild-type p53 signalling, triggering intrinsic apoptosis ( Del Mistro et al, 2022 ).…”

“…Defactinib is shown to be safe in healthy subjects, and has demonstrated efficacy against advanced malignancies in phase I trials (NCT02913716, NCT02546531 and NCT01943292). Interestingly, in a study utilising melanoma cells from patients who relapsed following treatment with BRAF or MEK targeted inhibitors, treatment with the FAK inhibitor (FAKi) defactinib was able to resensitise cells to killing by MAPK pathway inhibition ( Del Mistro et al, 2022 ). Other FAKi yet to be examined in melanoma are summarised in Table 2 .…”