New strategies for targeting kinase networks in cancer

Abstract

Targeted strategies against specific driver molecules of cancer have brought about many advances in cancer treatment since the early success of the first small-molecule inhibitor Gleevec. Today, there are a multitude of targeted therapies approved by the Food and Drug Administration for the treatment of cancer. However, the initial efficacy of virtually every targeted treatment is often reversed by tumor resistance to the inhibitor through acquisition of new mutations in the target molecule, or reprogramming of the epigenome, transcriptome, or kinome of the tumor cells. At the core of this clinical problem lies the assumption that targeted treatments will only be efficacious if the inhibitors are used at their maximum tolerated doses. Such aggressive regimens create strong selective pressure on the evolutionary progression of the tumor, resulting in resistant cells. High-dose single agent treatments activate alternative mechanisms that bypass the inhibitor, while high-dose combinatorial treatments suffer from increased toxicity resulting in treatment cessation. Although there is an arsenal of targeted agents being tested clinically and preclinically, identifying the most effective combination treatment plan remains a challenge. In this review, we discuss novel targeted strategies with an emphasis on the recent cross-disciplinary studies demonstrating that it is possible to achieve antitumor efficacy without increasing toxicity by adopting low-dose multitarget approaches to treatment of cancer and metastasis.

Keywords: cancer therapy; cell signaling; combination therapy; drug resistance; inhibitor; kinase network; mathematical modeling; mitogen-activated protein kinase (MAPK); receptor tyrosine kinases; targeted therapy.

Figure 1

Extensive cross talk between the oncogenic MAPK, PI3K/AKT, and JAK/STAT signaling pathways and vertical versus horizontal modes of inhibition. Vertical inhibition consists of combining two or more inhibitors targeting the same linear pathway (e.g., an EGFR inhibitor paired with a MEK inhibitor). Positive and negative feedbacks between different components of the MAPK, PI3K/AKT, and JAK/STAT signaling pathways allow for compensatory activation of one pathway when another is inhibited, which leads to tumor resistance. Horizontal inhibition mode aims to solve this resistance problem by targeting different pathways that function in parallel to regulate the same tumor-associated phenotype, such as a MEK inhibitor paired with AKT or PI3K inhibitor.

Figure 2

Mechanisms of drug resistance in cancers. Oncogenic signaling pathways are composed of receptors (growth factor receptors such as receptor tyrosine kinases, “RTK”s, cytokine receptors, or G-protein-coupled receptors), kinases (“K”), effectors (“E”, e.g., transcription factors) that regulate oncogenic gene expression. Resistance to an inhibitor targeting an oncogenic kinase (indicated by the green blunt-end line targeting K1) can develop by (1) amplification or constitutively activating mutation of upstream receptors that ultimately increase downstream oncogenic signaling and output (indicated by multiple arrows) (2), mutational changes in K1 that makes it resistant to drug binding, or activation of other isoforms of K1 (K1′) that are unaffected by the inhibitor (3), activation of parallel pathways (such as K4/K5 signaling) that can be triggered by the same receptor but bypass the initial pathway (K1/K2/K3) targeted by the drug, or (4) activation of independent pathways that are unaffected by the drug and can achieve similar oncogenic phenotype (RTK2/K6 signaling).

Figure 3

Strategies for targeting interconnected oncogenic networks using single or multiple targeted agents.A, hypothetical oncogenic network that drives tumor growth and metastasis. Each node in the network represents a kinase/gene that interacts positively or negatively with other downstream and upstream nodes within the network. Oncogenic networks are composed of numerous positive and negative feedback mechanisms that constitute an extensive cross talk between different biological pathways. Each node has the potential to activate an alternative compensatory pathway or network due to inherent redundancy in oncogenic signaling pathways. B, targeting a single node at a low dose to avoid drug-associated toxicity results in low or no efficacy as the oncogenic signaling is not sufficiently blocked. C, high-dose targeting of an individual node can inhibit pathway activity and show initial antitumor efficacy. However, this strategy usually results in activation of alternative pathways and networks that ultimately cause drug resistance. D, vertical inhibition of a linear pathway at multiple nodes not only increases drug-associated toxicity, but also increases pressure and resistance mechanisms. The therapeutic efficacy might be stronger in the dual setting, but the activation of adaptive compensatory networks is also more robust. E, targeting different pathways with high-dose combinations is still prone to toxicity and resistance as compensatory signaling mechanisms are still activated. F, targeting multiple nodes within an oncogenic network at low doses not only effectively reduces the overall oncogenic output of the network, but also prevents activation of compensatory networks and avoids resistance. This strategy also minimizes drug toxicity that usually associated with multidrug combinations since each inhibitor is used at low doses.

Figure 4

Summary of effective low-dose multidrug combinations.A, simplified network diagram showing the oncogenic MAPK and AKT signaling networks. The nodes displayed indicate the core signaling modules and are not meant to represent the entire network. Each node represents a kinase and the functional relationships between each kinase pair are indicated with arrows (for activation) and blunt-end lines (for inhibition). RAF-MEK-ERK cascade as well as the PI3K-AKT-mTOR cascade can be activated by receptor tyrosine kinases such EGFR, HER2, and ALK or by other kinases such as PAK1. Other components of the MAPK network (e.g., p38 and JNK signaling) can be induced by cellular stress signals such as hypoxia, nutrient deficiency, or unfolded protein accumulation in the endoplasmic reticulum. Panels B–D represent recently suggested low-dose multidrug treatment approaches that reduce the oncogenic output of the MAPK and AKT networks. B, low-dose combinations suggested by Yesilkanal et al.: p38i+JNKi, MEKi+MLKi, or p38i+JNKi+MEKi+MLKi (4D-MAPKi). C, low-dose combinations suggested by Neto et al.: RAFi+MEKi+ERKi, EGFRi+RAFi+MEKi+ERKi, ALKi+RAFi+MEKi+ERKi, or HER2i+PI3Ki+AKTi+mTORi. D, low-dose combinations suggested by Ozkan-Dagliyan et al.: RAFi+ERKi, RAFi+ERKi+PAKi, or RAFi+ERKi+AKTi. TAOK, Thousand and One Amino Acid Protein Kinase.