Reversing the consequences of oncogenic Ras is a fundamental problem in cancer therapeutics. Somatic RAS mutations are highly prevalent in many human cancers that respond poorly to current treatments, including carcinomas of the lung, pancreas, and colon; melanoma; and myeloid leukemia (for review, see Schubbert et al. 2007). At first glance, oncogenic Ras is an appealing target for rational drug discovery as the mutant protein is a membrane-associated signaling molecule that is expressed at robust levels in primary tumor cells. However, targeting oncogenic Ras is extremely challenging in practice due to the nature of the Ras cycle and the functional consequences of oncogenic mutations (for review, see Vetter and Wittinghofer 2001; Downward 2003). Ras relies on an intrinsic GTPase activity to terminate signaling by hydrolyzing GTP to GDP. This “off” reaction is relatively inefficient, but is accelerated thousands of fold by the GTPase-activating proteins (GAPs) neurofibromin and p120 GAP, which stabilize a transition state between Ras-GTP and Ras-GDP. Cancer-associated amino acid substitutions at codons 12, 13, and 61 both impair intrinsic Ras GTPase activity and confer resistance to GAPs. In principle, an effective small molecule therapy must therefore restore enzymatic activity within a highly constrained phosphate-binding loop of the oncoprotein without deregulating normal Ras or related cellular GTPases. Given these grim biochemical realities, drug discovery efforts have primarily focused in two areas: (1) blocking enzymes such as farnesyl transferase, which catalyze post-translational modifications of Ras that are essential for membrane targeting; and (2) developing inhibitors of downstream kinases such as MEK, Akt, and mTOR. Inherent in these strategies is the notion that reversing the growth of Ras-driven malignancies inevitably requires interrupting aberrant cell-intrinsic signaling networks. However, despite substantial effort, there are currently no agents that effectively counter the biochemical consequences of oncogenic Ras. A provocative paper by Ancrile et al. (2007) in the July 15 issue of Genes and Development suggests that interfering with the ability of Ras-driven tumors to modulate the behaviors of other cells in the microenvironment could represent a viable therapeutic approach. The current work was inspired, in part, by a previous study showing that HRAS-transformed HeLa cells secrete the cytokine interleukin 8 (IL8), which contributes to tumor growth in immunodeficient mice by promoting angiogenesis (Sparmann and Bar-Sagi 2004), and by the reports of elevated levels of another cytokine, interleukin 6 (IL6), in the sera of patients with pancreatic cancer (Wigmore et al. 2002). Ancrile et al. (2007) harnessed a tractable system for transforming primary cells with a defined set of genes that includes SV40 T/t antigens, the telomerase catalytic subunit hTERT, the p110 isoform of phosphoinositide-3-OH (PI-3) kinase fused to a CAAX membrane localization sequence, and a regulatable HRAS oncogene (Lim and Counter 2005). Inducing H-Ras protein expression resulted in morphologic transformation and a tumorigenic phenotype, which was associated with dramatic up-regulation of IL6 production in multiple cell types. Moreover, reducing IL6 levels through the use of short hairpin RNA (shRNA) knockdown technology markedly attenuated tumorigenesis in vivo. Interestingly, Ancrile et al. (2007) present data that argue strongly against autocrine signaling as the reason that IL6 enhances tumor growth. Instead, the data support a paracrine mechanism through which tumor-produced IL6 acts on infiltrating cells in the tissue microenvironment (see Fig. 1). In related studies, these authors observed attenuated tumor formation in IL6 mutant mice that are exposed to a well-established model of skin carcinogenesis. They also showed that IL6 knockdown altered the growth of kidney and mesenchymal cancer cell lines. These experiments support the general principle of targeting the microenvironment as a strategy for inhibiting the growth of tumors expressing oncogenic Ras. This idea is consistent with elegant studies of Schwann cell tumorigenesis in Nf1 mutant mice. The Nf1 tumor suppressor gene encodes neurofibromin, a GAP for Ras, and inactivating this gene in the Schwann cell lineage deregulates Ras signaling and results in tumor formation, which is dependent on aberrant cytokine signaling between the tumor and infiltrating haploinsufficient mast cells (Zhu et al. 2002; Yang et al. 2003). The data of Ancrile et al. (2007) also raise new questions. First, it is uncertain how oncogenic Ras expression induces IL6 production and, in particular, whether this is consequence of activating Ras/Raf/MEK/ERK, Ral-GDS, PI3 kinase/Akt, and/or other effectors of Ras-GTP. Second, whereas IL6 production by tumorigenic cells is asCorresponding author. E-MAIL shannonk@peds.ucsf.edu; FAX (415) 502-5127. Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1587907.
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Aug 20, 2008
Claudine M Carvalho + 5
Open Access
