Overcoming resistance to targeted therapy with immunotherapy and combination therapy for metastatic melanoma

Abstract

Resistance to targeted therapy is an ongoing problem for the successful treatment of Stage IV metastatic melanoma. For many patients, the use of targeted therapies, such as BRAF kinase inhibitors, were initially promising yet resistance inevitably occurred. Even after combining BRAF kinase inhibitors with MEK pathway inhibitors to offset re-activation of the MAP kinase pathway, resistance is still documented. Similarly, outcomes with immune checkpoint inhibitors as monotherapy were optimistic for some patients without relapse or progression, yet the majority of patients undergoing monotherapy have progressive disease. Will immunotherapy and combination therapy trials overcome resistance in metastatic melanoma? In an effort to treat resistant disease, new clinical trials evaluating the combination of immunotherapy with other therapies, such as kinase inhibitors, adoptive cell therapy, chimeric CD40 ligand to boost costimulation, or a tumor-specific oncolytic virus enhancing granulocyte macrophage colony-stimulating factor (GM-CSF) expression, are currently underway. Updated studies on the mechanisms of resistance, immune escape and options to reinvigorate immune cells support the continued discovery of new and improved forms of therapy.

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

“…The EC50 (50% effective concentration) and EC75 (75% effective concentration) or EC90 (90% effective concentration) are shown (n = 3-6). *P < 0.05 as determined by a one-sample Student's t-test treatments to overcome resistance and increase response rates [7]. Strategies include targeting other forms of cell death such as necroptosis [46], inhibiting MAPK reactivation that occurs following targeted therapy treatment, and concomitantly inhibiting other pathways including the PI3K/Akt/mTOR [47,48].…”

“…Given that TM is available as a 6 mg pill administered twice daily, the doses we used in our in vivo studies are within the physiological range. Furthermore, as the compound synergized with Vemurafenib and other kinase inhibitors currently used in melanoma patients with late-stage disease, this is likely a favorable point of clinical entry especially since most patients eventually develop resistance to Vemurafenib and other kinase inhibitors [7,47]. Furthermore, as the BRAF WT cohort of patients are a diverse group, treatment options are much less clear cut [44,58] although immunotherapies, as with BRAF V600E melanoma are a promising albeit costly treatment approach [59].…”

“…However, resistance to targeted therapies as well immunotherapy where bio-markers of response are not yet wellestablished [5,6], present challenges in the treatment of melanoma. Although combinatorial approaches of the various targeted therapies together with immunotherapies are underway [7], the high-costs [5] associated with immunotherapy highlights an urgent need for novel anti-melanoma therapeutic options. The application of drugs used for alternate diseases as novel anti-cancer therapeutics, known as drug repositioning, has been successfully implemented in the clinical setting [8] and these compounds can be a rich potential source of novel, readily available anti-cancer therapeutics.…”

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

“…Moreover, the cytostatic effect of the drug imposes that such therapy should be administered lifelong. In many tumor types, the combination of targeted therapy with other agents, including immunotherapy, has shown promising results in enhancing drug efficacy, overcoming resistance and reducing side effects (Keller et al 2017). Thus, it is possible that RET-targeting TKI, together with immune checkpoint or IDO inhibitors, may represent a novel therapeutic option for patients with advanced and progressive MTC.…”

Unconventional Approaches to Modulating the Immunogenicity of Tumor Cells

“…And, several pan-HDAC inhibitors, such as sodium valproate, etinostat, panobinostat, and vorinostat, have all been shown in vivo to enhance the antitumor efficacy of checkpoint inhibitory antibodies, as well as promote activated T cell infiltration into the tumors (Booth, Roberts, Poklepovic, & Dent, 2017; Booth, Roberts, Poklepovic, Kirkwood, & Dent, 2017; Christiansen et al, 2011; Gameiro, Malamas, Tsang, Ferrone, & Hodge, 2016; Hornig, Heppt, Graf, Ruzicka, & Berking, 2016; Kroesen et al, 2016; Vo et al, 2009; West & Johnstone, 2014; West et al, 2013). Tumor types tested in these studies are diverse and include melanoma, breast, colorectal, glioblastoma, and hepatoma (Chae, Wang, Nimeiri, Kalyan, & Giles, 2017; Huang et al, 2017; Keller, Zhang, Li, Schaider, & Wells, 2017; Monnot & Romero, 2017; Rai et al, 2017). …”