Targeting Pathways Downstream of KRAS in Lung Adenocarcinoma

Zehua Zhu; Hadrien G Golay; David A Barbie


Pharmacogenomics. 2014;15(11):1507-1518. 

In This Article

Abstract and Introduction


Oncogenic KRAS activation is responsible for the most common genetic subtype of lung cancer. Although many of the major downstream signaling pathways that KRAS engages have been defined, these discoveries have yet to translate into effective targeted therapy. Much of the current focus has been directed at inhibiting the activation of RAF/MAPK and PI3K/AKT signaling, but clinical trials combining multiple different agents that target these pathways have failed to show significant activity. In this article, we will discuss the evidence for RAF and PI3K as key downstream RAS effectors, as well as the RAL guanine exchange factor, which is equally essential for transformation. Furthermore, we will delineate alternative pathways, including cytokine activation and autophagy, which are co-opted by oncogenic RAS signaling and also represent attractive targets for therapy. Finally, we will present strategies for combining inhibitors of these downstream KRAS signaling pathways in a rational fashion, as multitargeted therapy will be required to achieve a cure.


Constitutively active signaling downstream of KRAS is a fundamental driver of lung tumorigenesis. KRAS is the most commonly mutated oncogene in lung adenocarcinomas, ranging in incidence from 15 to 40% across different studies.[1] The majority of oncogenic KRAS mutations are located in codons 12, 13, 61 and 146, and consist of missense transversions associated with smoking. An additional large fraction of lung adenocarcinomas engage wild-type KRAS signaling via upstream receptor tyrosine kinase activation or other means. Consistent with this observation, mutations in KRAS are generally mutually exclusive with genetic alterations in receptor tyrosine kinases such as EGFR or ALK.

Despite over 30 years of research and a detailed molecular understanding of the pathways that KRAS activates, targeted KRAS therapies that provide clinical benefit have yet to be designed. In part, this challenge relates to the fact that KRAS itself, a single-subunit small GTPase protein, has remained difficult to inhibit with small molecules. For example, despite their initial promise, farnesyltransferase inhibitors that prevent KRAS membrane anchorage have had limited activity in the clinic.[2] Although other molecules that target KRAS membrane localization[3] or inhibit the guanine nucleotide-binding site in a covalent fashion are being developed,[4,5] these strategies have yet to be validated therapeutically. Instead, current attempts to target KRAS in the clinic have focused on the inhibition of downstream signaling pathways.

In this article, we will focus on the specific gene products and signaling pathways downstream of KRAS that are critical for cellular transformation and for maintenance of lung tumorigenesis. We will detail the evidence for targeting the well-established KRAS signaling effectors in the clinic and novel strategies for identifying and disrupting codependent pathways. Furthermore, given the complexity of KRAS signal transduction, it is increasingly recognized that combination therapies will be required in order to block the multiple effector pathways that KRAS utilizes to drive and sustain lung tumorigenesis. Previous reviews have discussed in depth the efforts to cotarget the MAPK and PI3K pathways, as well as early functional genomic studies designed to identify synthetic lethal targets.[6] Since clinical trials of MEK and PI3K inhibitors have yielded largely disappointing results and certain novel approaches to inhibiting the pathways that are co-opted by KRAS have shown promise, we will focus on the next generation of KRAS-targeted studies that are entering the clinic. We will also highlight how maximizing the inhibition of parallel pathways and/or those linked by feedback, while minimizing overlapping toxicities, likely represents a key feature to achieving therapeutic success.