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Challenges in targeting the KRAS pathway Oncogenic Ras (KRAS) is one of the most prevalent somatic aberrations in cancer [1]. KRAS acts as a molecular switch that recruits and activates a repertoire of proteins necessary for cell proliferation, desmoplasia, maintenance of tumor heterogeneity (cancer stem-like cells), tumor aggressiveness and metastases [2]. Even though there is a consensus regarding the importance of KRAS in cancer, the absence of a typical drug binding pocket in its structure has kept KRAS as an elusive target for more than three decades [3]. While targeted agents against important members downstream of KRAS such as PI3K, AKT, MEK and EGFR do show initial response, resistance develops in almost all instances, thereby making these targets ineffectual [4]. Therefore, in order to overcome this challenge, newer druggable avenues either through the Ras structure itself or through critical direct interacting partners or downstream effectors of this master oncogenic regulator are urgently needed [5]. This article builds the case for the p21-activated kinases (PAKs) in general and PAK4 in particular as unique druggable avenues that are downstream of KRAS signaling.

In spite of the expensive preclinical testing, the consistent failure to translate many promising targeted drugs from the laboratory bench to the clinic raises the question of whether the single-pathway drug-discovery strategies offer the correct perspective. As revealed by network biology, cancers harbor robust biological networks that are inherently resistant to changes, such as those induced by drugs with very narrow mechanisms of action. Therefore, network pharmacology strategies, the treatment of cancer by modulating more than one target, are needed. Different promiscuous approaches targeting multiple avenues within cancer-associated networks, such as the pleiotropic natural products, are emerging. Nevertheless, there is a long way before such ‘proof-of-concept strategies’ can be successfully applied in the clinical setting. This article provides a perspective on the current challenges in drug discovery, the reasons for high failure rates and how network pharmacology can aid the successful design of agents against cancer.