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Combinatorial strategies to target RAS-driven cancers

Nature Reviews Cancer volume 24, pages 316–337 (2024)Cite this article

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Abstract

Although RAS was formerly considered undruggable, various agents that inhibit RAS or specific RAS oncoproteins have now been developed. Indeed, the importance of directly targeting RAS has recently been illustrated by the clinical success of mutant-selective KRAS inhibitors. Nevertheless, responses to these agents are typically incomplete and restricted to a subset of patients, highlighting the need to develop more effective treatments, which will likely require a combinatorial approach. Vertical strategies that target multiple nodes within the RAS pathway to achieve deeper suppression are being investigated and have precedence in other contexts. However, alternative strategies that co-target RAS and other therapeutic vulnerabilities have been identified, which may mitigate the requirement for profound pathway suppression. Regardless, the efficacy of any given approach will likely be dictated by genetic, epigenetic and tumour-specific variables. Here we discuss various combinatorial strategies to treat KRAS-driven cancers, highlighting mechanistic concepts that may extend to tumours harbouring other RAS mutations. Although many promising combinations have been identified, clinical responses will ultimately depend on whether a therapeutic window can be achieved and our ability to prospectively select responsive patients. Therefore, we must continue to develop and understand biologically diverse strategies to maximize our likelihood of success.

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Fig. 1: Conceptual approaches for developing combination strategies.
Fig. 2: The RAS signalling pathway and inhibitors in clinical and preclinical development.
Fig. 3: Combinatorial strategy type I: vertical inhibition.
Fig. 4: Combinatorial strategy type II: inhibition of protective adaptive responses.
Fig. 5: Combinatorial strategy type III: co-targeting a critical downstream node.
Fig. 6: Combinatorial strategy type IV: capitalize on other cancer-associated vulnerabilities.

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Acknowledgements

This work was supported by R01CA111754 and the Ludwig Center at Harvard (K.C.). L.S. was supported by a Landry Cancer Biology Research Fellowship.

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Author notes

  1. These authors contributed equally: Naiara Perurena, Lisa Situ.

Authors and Affiliations

  1. Genetics Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Naiara Perurena, Lisa Situ & Karen Cichowski

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Naiara Perurena, Lisa Situ & Karen Cichowski

  3. Ludwig Center, Harvard Medical School, Boston, MA, USA

    Karen Cichowski

Authors
  1. Naiara Perurena
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  2. Lisa Situ
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  3. Karen Cichowski
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Contributions

All authors researched data for the article, contributed substantially to discussion of the content and wrote the article. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Karen Cichowski.

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Competing interests

K.C. is an adviser at Genentech and serves on the scientific advisory board of Erasca, Inc. N.P. and L.S. declare no competing interests.

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Nature Reviews Cancer thanks Julian Downward, Rene Bernards and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Glossary

Adaptive responses

Cell-intrinsic protective mechanisms that are triggered in response to a given drug exposure and allow tumour cells to survive.

Allele-specific inhibitors

A class of inhibitors that selectively target specific mutant alleles of KRAS, NRAS or HRAS oncoproteins and do not have activity against wild-type isoforms.

Anchor agent

In the context of this Review, an agent that suppresses a core component of the RAS pathway and is co-administered with a second drug against a different target as part of a combination therapy.

Class I HDAC inhibitors

Drugs that target class I histone deacetylases (HDAC1, HDAC2, HDAC3, HDAC8), enzymes that are located in the nucleus and remove acetyl groups from the chromatin.

Converging oncogenic targets

Gene products that function downstream of multiple oncogenic pathways and whose inhibition may allow simultaneous suppression of several oncogenic processes.

Cytostasis

A lack of change over time in the number of tumour cells, which can reflect a balance between cell proliferation and cell death.

Degraders

A class of small molecule inhibitors that bring a target into close proximity with an E3 ubiquitin ligase to promote polyubiquitination and subsequent proteasomal degradation of the target.

Ferritinophagy

A selective form of autophagy that involves the degradation of ferritin and subsequent mobilization of iron.

Hydroxychloroquine

(HCQ). A drug that inhibits the recycling of cellular components through autophagy by preventing lysosomal acidification and hindering autophagosome–lysosome fusion.

Macropinocytosis

A form of endocytosis in which the plasma membrane non-selectively engulfs extracellular fluid to internalize and degrade macromolecules.

Metabolic stress

A state of stress in which cellular bioenergetic and biosynthetic demands impact metabolic homeostasis and result in the underproduction or overproduction of critical metabolites.

Mitotic stress

A state of stress in which dysregulated mitosis leads to the mis-segregation of chromosomes during uncontrolled cell division.

Molecular glues

A class of small molecules that induce or stabilize the interaction between two given proteins.

Noonan-like syndrome

A disorder caused by germ-line mutations in SHOC2 that is characterized by phenotypes similar to those observed in the RASopathy Noonan syndrome that include loose anagen hair, hyperpigmentation, and craniofacial and cardiac anomalies.

On-target mechanisms of resistance

Resistance that occurs through mutations in genes or pathways directly targeted by a drug.

Oxidative stress

An imbalance between the production of reactive chemical species and the antioxidant response that promotes various signalling pathways but can lead to intracellular damage.

Proteotoxic stress

An imbalance of protein levels that can result from dysregulated protein translation, protein folding or protein degradation and apply strain on the unfolded protein response or proteasomal degradation pathway.

RASopathy

A group of medical syndromes characterized by germ-line mutations in genes of the RAS pathway that lead to deregulated pathway activity.

Replication stress

A state of genomic dysregulation in which triggers such as DNA damage lead to the stalling of replication forks during DNA replication.

Synthetic lethality

An interaction between two genes wherein perturbation of each single gene is not lethal on its own whereas concurrent perturbations of both genes induce cell death.

Therapeutic window

The range of drug concentrations in which the therapeutic effect is achieved with minimal toxicity.

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Perurena, N., Situ, L. & Cichowski, K. Combinatorial strategies to target RAS-driven cancers. Nat Rev Cancer 24, 316–337 (2024). https://doi.org/10.1038/s41568-024-00679-6

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