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Page 12 Conroy et al. Cancer Drug Resist 2021;4:543-58 https://dx.doi.org/10.20517/cdr.2021.07

CONCLUSION AND FUTURE DIRECTIONS
Effective and safe inhibition of RAS was considered a holy grail for cancer researchers decades ago, and it
remains so today. While extraordinary advances have been made in our understanding of RAS and
carcinogenesis - as well as methods of targeting its downstream effectors - the direct inhibition of RAS does
not yet have a role in everyday practice. However, our deeper understanding of molecular pathogenesis is
the foundation on which that future progress will be built, and effective treatments are now close.

The unmet need for proven therapies in this setting is clear, given the prevalence of RAS mutations in
common cancers, many of which are highly fatal. Our recognition of the structure and clinical significance
of diverse RAS isoforms represents a major step forward, of relevance to all future efforts at RAS targeting.
Their importance is clear when considering candidate inhibitors of RAS plasma membrane localization,
which are now reaching the clinic. Even individual isoforms, like K-RAS, have a range of possible mutations
[94]
with different responses to targeted therapies . Therefore, those designing clinical trials should carefully
consider the need for isoform and mutation-specific approaches.

The development of inhibitors of RAS effector signalling, which are in widespread clinical practice, is an
example of the concrete achievements of research in this area. This success has been tempered over time by
failures, many of which can be attributed to misconceptions of RAS signalling pathways as unidirectional
and linear. A more nuanced appreciation of these as delicately balanced signalling networks can help
researchers refine their approach, and may warrant increased focus on drug combinations, as seen in trials
[52]
involving inhibitors of MEK and autophagy .

Possibly showing greater promise than any of these initiatives, however, is efforts at direct targeting of RAS.
The past 12 months has seen breakthroughs in this field that have been sought for years, vindicating decades
of basic scientific endeavour. Successes here belie outdated dogma describing RAS as “undruggable”,
demonstrating that drug exposure associated with preclinical efficacy can be achieved safely in patients .
[95]
However, these studies also raise questions - why did response rates to Sotorasib vary between cancers
despite identical mutations, and what provoked early progression in some patients after an initial response?
It is suggested that tumour heterogeneity or driver mutations alternative to K-RAS(G12C) may be the key to
understanding this and that, as with inhibition of RAS effector signalling, drug combinations may be the
[78]
next step . In addition, optimizing monotherapy by developing inhibitors with higher affinity for inactive
KRAS(G12C) or the use of pulsatile therapy has been suggested as approaches to maximise therapeutic
effect .
[96]
In summary, a more textured understanding of RAS pathogenesis emerging from decades of basic scientific
research has led to a more refined approach to RAS inhibition, which is now beginning to bear fruit. The
coming months and years will hopefully take these efforts “over the line” to the routine use of effective
therapeutics in the clinic setting, but it will be a long time before we have fully tapped the potential of RAS
inhibition.

DECLARATIONS
Authors’ contributions
All authors made substantial contributions to drafting the article, revising it and giving final approval prior
to submission.