Mutations in the KRAS oncogene drive proliferation of 30% of all human cancers, for which effective targeted therapies are still urgently needed. In a recent study published in Cell Research, Cheng et al. report the identification of a new player in the KRAS game which could pave the road for yet unexplored therapeutic strategies.
The first human RAS oncogene was discovered some 40 years ago. Since then, research has focused on understanding the biology and biochemistry of this family of tumor-promoting genes, of which KRAS is the most prevalently mutated member. We have learned that RAS works as a molecular switch that transduces mitogenic signals emanating from the cell surface and activates one of the most potent pro-proliferative routes, the Mitogen Activated Protein Kinase (MAPK) pathway. It has also become evident that once the RAS switch is mutated, this mitogenic signaling cascade goes out of control, initiating and sustaining tumor progression.1 Unfortunately, it has also become clear that RAS is a protein difficult to target. This is due both to its extremely high affinity to its co-factor GTP (which impairs the design of a competitive inhibitor), and to its smooth surface lacking obvious “pockets” for small-molecule binders.2
Lately, after a couple of decades of stagnation, the RAS field has seen a major revival, due to the first cleverly designed KRAS-G12C-specific inhibitors entering the clinical space. Moreover, equally promising compounds targeting other RAS mutants are also under preclinical or early clinical development.3 The first experiences in the clinic with the new KRAS inhibitors show a clear improvement in the management of KRAS-mutant tumors (in particular of lung cancer).4,5 Nevertheless, they also indicate that even this sophisticatedly targeted therapy is not immune to the curse of resistance.6 Therefore, rational combinations that delay or prevent said resistance are currently being investigated. In this context, every new insight in RAS biology could potentially lead to a much-needed new therapeutic agent for combination with other MAPK-targeted drugs.
Just when we thought that 4 decades of RAS research had revealed just about everything there is to know about this cancer signaling pathway, an unexpected new player is described in a recent study of Cell Research. Cheng et al. identified an unlikely suspect, a seemingly non-coding RNA named Linc00673, as a new regulator of RAS signaling.7 It has been reported previously that some non-coding RNAs do encode proteins, often using non-canonical translation start sites.8 Indeed, Linc00673 also turns out to encode a protein that the authors named RASON. Interestingly, RASON is often overexpressed in KRAS-mutant tumors. In particular, they showed that high RASON expression correlates with poor prognosis in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). The authors proceeded to investigate the biological function of RASON in PDAC models. Through a series of overexpression and loss of function experiments, they showed that RASON promotes tumor cell proliferation via regulation of RAS. Using classic immunoprecipitation and more sophisticated surface plasma resonance techniques, Cheng and colleagues showed that RASON can directly bind mutant RAS with high affinity. It is well established that RAS cycles between a GDP-bound inactive state and a GTP-bound active state. In this process, RAS is assisted by RAS-GEFs, which help exchanging GDP for GTP, and by RAS-GAPs, which catalyze the GTP hydrolysis. In their Cell Research paper, Cheng at al., showed that, through binding RAS with high affinity, RASON prevents recruitment of RAS-GAPs, and therefore locks RAS in its GTP-bound, active form, thus promoting downstream signaling and, ultimately, cell proliferation.
After having elucidated the biological function of this novel RAS regulator, the authors asked an important question: is RASON a potential therapeutic target? To address this, the authors use both PDAC patient-derived organoids and genetically engineered mouse models. They found that RASON suppression not only reduces tumor growth, but also sensitizes RAS-mutant cancer cells to EGFR inhibition. A recent finding is that even RAS-mutant tumors depend on upstream stimulation for RAS to transduce signals to downstream proteins.9 Thus, reducing the fraction of GTP-bound RAS increases the dependence on upstream activation of RAS by tyrosine kinases like EGFR. This finding is of potential clinical relevance, as patients having KRAS-mutant tumors are currently excluded from anti-EGFR treatment, because activating mutations of RAS makes them intrinsically resistant to EGFR inhibitors.10 The results presented in this study thus open the possibility of expanding the use of EGFR inhibitors to KRAS-mutant tumors, if it becomes possible to inhibit RASON activity.
As RASON is a novel protein, no inhibitors currently exist that can prevent it from interacting with and activating RAS. Therefore, the authors used genetic tools to mimic loss of function of RASON in preclinical models. Using this approach, they provide a compelling data supporting that RASON is a promising cancer drug target. It will now be up to the pharmaceutical companies to develop such inhibitors. Possibly, degron technology could be useful to target the stability of the RASON protein. Additionally, such RASON inhibitors/degraders could represent a potential combination partner for the newly identified KRAS inhibitors, in particular for the clinically approved KRAS-G12C inhibitors sotorasib and adagrasib, for which we know that resistance will eventually occur. Preclinical validation of the combination with RASON inhibitors/degraders in KRAS-G12C-mutant cancer models will be needed to confirm the efficacy and tolerability of this dual therapy.
What is arguably the most surprising aspect of the research by Cheng and colleagues is the notion that 40 years of RAS research has not yet exhausted the list of RAS modulators. The disguise of RASON as a non-coding RNA made this nut hard to crack and the authors should be commended for their elegant detective work to uncover this novel player in RAS signaling.
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Mainardi, S., Bernards, R. RASON, a new player in cancer’s Premier League. Cell Res 33, 1–2 (2023). https://doi.org/10.1038/s41422-022-00750-7