Mitogen-Activated Protein Kinase Inhibitors and Immunotherapy in Cancer: Comparison
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Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy.

  • cancer
  • mitogen-activated protein kinase
  • T cells
  • Programmed cell death protein 1
  • Programmed death-ligand 1
  • cytotoxic T-lymphocyte-associated protein 4
  • T-cell anergy
  • immunotherapy

1. Introduction

Mitogen-activated protein kinase (MAPK) signaling is mediated by several MAPK family members, sharing several evolutionary-conserved domains [1]. Together, these events are contributing to a wide range of cellular function including proliferation [2], migration [3], angiogenesis [4], invasion [5], metastasis [6] and apoptosis [7]. Classically, MAPK signals are activated downstream of receptor tyrosine kinases, including epithelial growth factor receptor (EGFR) [8]. However, in cancer, MAPK signaling is commonly hyperactivated due to gain of function mutations in proto-oncogenes including B-Raf proto-oncogene, serine/threonine kinase (B-Raf) [9], neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) [10], Kirsten rat sarcoma viral oncogene homolog (KRAS) [11], Raf-1 proto-oncogene, serine/threonine kinase (RAF1) [12], or loss of function mutations to negative regulators including neurofibromatosis type 1 (NF1), in each case leading to enhanced cell proliferation and survival [13].
Previous reports suggest that MAPK signaling is essential for T-cell development [14][15], activation [15][16], proliferation and survival [16][17]. Unsurprisingly, MAPK signaling is also implicated in directing interactions between tumor cells and the surrounding T-cell infiltrate, though these roles are complex and often contradictory. For instance, MAPK signaling has been shown to suppress the expression of negative immune checkpoints such as programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in several cancers [17][18]. Similarly, various MAPK members down regulate T-cell costimulatory molecules such as tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), also known as CD134 or OX40 and tumor necrosis factor receptor superfamily member 9 (TNFRSF9) also known as CD137 or 4-1BB, thereby impeding T-cell activation and effector function [18][19].

2. MEK/ERK Inhibition

ERK was the first MAPK family member to be cloned and characterized [19][20], and is most commonly activated by the upstream RAS/RAF/MEK cascade [20][21]. ERK signaling regulates a variety of benign and malignant cell functions, including proliferation, differentiation, motility, and survival [21][22]. While the role of ERK signaling is well described in tumor cells, ERK is also crucial in the regulation of several aspects of T-cell biology, including positive/negative selection in the thymus [22][23]. In mature T-cells, ERK is activated following interaction between the T-cell receptor (TCR) and major histocompatibility complex (MHC) on an antigen-presenting cell [23][24], where it functions to direct the activation of a T cell [24][25] as well as interleukin-2 (IL-2) production and clonal expansion [25][26]. This is particularly true with respect to effector CD8+ T-cells, which are dependent on ERK signaling to remain functionally active [26][27]. Several selective inhibitors of ERK signaling are reported to have marked antitumor efficacy, including FR180204 [27][28], BVD523 [28][29], CC90003 [29][30], GDC-0994 [30][31] and MK-8353 [31][32]. BVD523 (Ulixertinib) specifically has been used in clinical trials, showing clear efficacy in patients who have been previously treated with immunotherapy [28][29]. Mitogen-activated protein kinase kinase (MEK, also known as MAP2K) is an upstream MAPK kinase family member that phosphorylates MAPK members ERK, p38 and JNK [32][33], though MEK is most clearly associated with ERK activation [33][34]. Accordingly, MEK/ERK has also been proposed as a potential target for therapy (Table 1).
Table 1.
MEK/ERK inhibitors and immunotherapy in cancer.

MEK/ERK Member

Inhibitor

Combination with Immunotherapy

Cancer Type

MEK1/2

Trametinib

4-1BB and OX40 agonist antibodies

Breast cancer [18][19]

Selumetinib

Anti-EGFR antibody

Lung adenocarcinoma [34][39]

G-38963

Anti-PD-L1 antibody

Colon carcinoma [35][40]

ERK1/2

BVD523

Positive outcomes in patients previously treated with immunotherapy

NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors [28][29]

3. JNK Inhibition

JNK proteins are also MAPK family members and were first discovered in the 1990s [36][41]. JNK signals are activated by several upstream MAPK members [37][42] as well as G-protein-coupled receptors (GPCRs) [38][43]. Like other MAPKs, JNK signaling pathways regulate several cellular functions [39][44]. Accordingly, JNK signals also appear to regulate T-cell differentiation and function [40][45], though the contributions of JNK signaling are re-multifaceted and context-dependent. For example, when thymocytes undergo apoptosis, JNK2 targets Jun proto-oncogene (c-JUN) to promote cell death, whereas during proliferation, JNK2 targets nuclear factor of activated T-cells (NFAT) to mediate DNA binding [41][46]. Further, JNK cooperates with MEKK2 signaling to direct IL-2 biosynthesis, serving crucial roles in TCR/CD3-mediated T-cell signaling [42][47]. Interestingly, JNK appears to differentially regulate CD4+ and CD8+ T-cell function [43][48].
However, there are several emerging JNK inhibitors, including SP600125 [44][49], AS601245 [45][50], CC-401 [46][51], AS602801 [47][52], D-JNKI-1 [48][53] and BI-78D3 [49][54], that are now showing early efficacy in various solid tumor types [50][55]. Interestingly, the JNK inhibitor SP600125 has been suggested to rescue cytotoxic T-lymphocytes from activation-induced cell death without diminishing their capacity to synthesize cytotoxic cytokines such as IFNγ [51][56]. Hence, while JNK is not yet substantiated as a viable target for combined immunotherapies, it warrants future consideration in combination with immune checkpoint inhibitors.

4. p38 MAPK Inhibition

The p38, another MAPK family member, also appears to have important roles in immune function. The p38 MAPK is activated by environmental stress as well as several inflammatory cytokines [52][57]. Like other MAPKs, the functions of p38 have been well-established in tumor cells, directing any number of cell processes including differentiation, migration, and inflammation [53][58]. Accordingly, p38 overexpression is associated with poor responses to conventional therapy in several cancers including breast cancer, nasopharyngeal carcinoma, gastric, and pancreatic cancer [54][55][56][57][59,60,61,62].
To date, a number of selective inhibitors of p38 MAPK have been synthesized including SCIO-469 [58][68], BIRB-796 [59][69], LY2228820 [60][70], VX-745 [61][71], SB203580 [62][72] and PH-797804 [63][73]. Several are beginning to show early efficacy in cervical [64][74], pancreatic, ovarian, [65][75] and breast cancers [60][70]. Additionally, p38 MAPK inhibition cooperated with anti-CD137 to promote antitumor T-cell responses in glioblastoma [66][76]. Further, p38 inhibition appears to increase the expression of OX40L and downstream OX40 signaling in dendritic cells (DCs), thereby potentiating effector T-cell function [67][77]. Hence, while the clinical utility of p38 inhibition also remains unclear, p38 inhibitors also warrant exploration in the setting of immune checkpoint inhibition.

5. Other MAPK Family Members

Several nonclassic MAPK family members also appear to have paramount roles in T-cell biology, and their inhibition may also warrant consideration as an adjuvant to immunotherapy. For example, Hematopoietic Progenitor Kinase-1 (HPK1) is a member of the MAP4K family expressed largely in hematopoietic cells [68][78], and acts upstream of MAPK signaling [69][79]. HPK1 has been reported to regulate both nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and activates JNK signaling pathway [70][80], and is associated with progression of gastrointestinal tumors [71][81]. The roles of HPK1 in T-cell function is now becoming clear.
Another upstream regulator of MAPK signaling, germinal center-like kinase (GLK or MAP4K3) belongs to serine/threonine-protein kinase, Ste20 family of protein kinases [72][84], and may also have important roles in T-cell function. GLK is activated by stimuli including ultraviolet radiation and several proinflammatory cytokines [72][84], and has clear roles in the pathogenesis of both autoimmune disease and cancer [73][85]. Clinically, GLK overexpression predicts poor overall and progression-free survival in non-small-cell lung carcinoma (NSCLC) [74][86], though the mechanisms through which GLK contributes to disease pathogenesis are not clear at this time. However, emerging evidence suggests that GLK regulates T-cell activation via IL-17A signaling [75][87]. Accordingly, the GLK inhibitor, Verteporfin, has been approved by FDA in macular degeneration of eyes [76][88] and may warrant exploration in cancer.

Mixed lineage kinases (MLKs) are member of MAP3K family that contain serine/threonine and tyrosine kinase activities [771][782]. Recently, a member of MLK family, MLK3 has been reported to be involved in regulation of T cell activation and cytotoxicity  [793]. Furthermore, it has also been reported that genetic loss or pharmacological inhibition of MLK3 induces CD70-mediated apoptosis in CD8+ T cells [804]. Considering this fact a rationalized combination of MLK3 and CD70 antagonists showed anticancer efficacy in triple-negative breast cancer pre-clinical model [804]. Further studies are required to explore role of several MAPKs upstream regulators in cancer and immunotherapy.

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