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Rare molecular subtypes of lung cancer

Nature Reviews Clinical Oncology volume 20, pages 229–249 (2023)Cite this article

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Abstract

Oncogenes that occur in ≤5% of non-small-cell lung cancers have been defined as ‘rare’; nonetheless, this frequency can correspond to a substantial number of patients diagnosed annually. Within rare oncogenes, less commonly identified alterations (such as HRAS, NRAS, RIT1, ARAF, RAF1 and MAP2K1 mutations, or ERBB family, LTK and RASGRF1 fusions) can share certain structural or oncogenic features with more commonly recognized alterations (such as KRAS, BRAF, MET and ERBB family mutations, or ALK, RET and ROS1 fusions). Over the past 5 years, a surge in the identification of rare-oncogene-driven lung cancers has challenged the boundaries of traditional clinical grade diagnostic assays and profiling algorithms. In tandem, the number of approved targeted therapies for patients with rare molecular subtypes of lung cancer has risen dramatically. Rational drug design has iteratively improved the quality of small-molecule therapeutic agents and introduced a wave of antibody-based therapeutics, expanding the list of actionable de novo and resistance alterations in lung cancer. Getting additional molecularly tailored therapeutics approved for rare-oncogene-driven lung cancers in a larger range of countries will require ongoing stakeholder cooperation. Patient advocates, health-care agencies, investigators and companies with an interest in diagnostics, therapeutics and real-world evidence have already taken steps to surmount the challenges associated with research into low-frequency drivers.

Key points

  • Many ‘rare’ molecular subtypes of lung cancer individually account for a substantial number of patients diagnosed annually around the world.

  • An incredible diversity of molecular subtypes of lung cancer exists; mechanistically, these can be classified into mutations, fusions and copy number changes.

  • Alterations involving receptor tyrosine kinases and MAPK pathway members can share structural and/or oncogenic features; conversely, other alterations have distinct mechanisms of oncogenesis such as effects on RNA splicing or epigenetic processes.

  • Optimizing the identification of rare driver oncogenes requires both clinicopathological approaches that are feature-agnostic and tailored approaches to patient selection, tumour and plasma interrogation, DNA and RNA sequencing, and more unbiased profiling.

  • Targeted therapy approvals were previously focused on certain alterations to the point of saturation and dominated by small-molecule tyrosine kinase inhibitors; approved and investigational antibody-based therapies are now becoming more widely used.

  • Oncogene-driven advocacy, the adoption of contemporary trial designs, expedited regulatory pathways for drug development, and real-world evidence generation are all crucial steps towards promoting research and expediting the approval of drugs for rare oncogene-driven lung cancers.

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Fig. 1: Frequency of ‘rare’ lung cancers.
Fig. 2: Receptor tyrosine kinase gene mutations.
Fig. 3: RAS and MAPK family mutations.
Fig. 4: Fusion circos plot.
Fig. 5: Fusions structure, signalling and localization.
Fig. 6: Rational drug design trends.
Fig. 7: Stakeholder cooperation.

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Acknowledgements

The authors to acknowledge their senior editor at Memorial Sloan-Kettering Cancer Center, C. Wilhelm, for the exceptional editorial support he provided for this manuscript. This work was supported in part by an NIH award P30 CA008748. E.C. gratefully acknowledges support from the Lung Cancer Research Foundation (LCRF), the Madelon Ravlin Grant Memorial Award from the Woman’s Cancer Association of the University of Miami and the Tumor Biology Intra-Programmatic Pilot Award from the Sylvester Comprehensive Cancer Center. E.C. also thanks the LCRF for the 2022 William C. Rippe Award.

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  1. These authors contributed equally: Guilherme Harada, Soo-Ryum Yang.

  2. These authors jointly supervised this work: Emiliano Cocco, Alexander Drilon.

Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Guilherme Harada & Alexander Drilon

  2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Soo-Ryum Yang

  3. Department of Biochemistry and Molecular Biology/Sylvester Comprehensive Cancer Center, University of Miami/Miller School of Medicine, Miami, FL, USA

    Emiliano Cocco

  4. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    Alexander Drilon

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Competing interests

G.H. has acted as an adviser to AstraZeneca, Bayer, Lilly, Merck and MSD. S.-R.Y. has received honoraria from PRIME Education LLC. E.C. has acted as a consultant of ENTOS Inc., and has received research funding from ERASCA and InnoCare pharma. A.D. has acted as an adviser to Abbvie, AiCME, Amgen, Applied Pharmaceutical Science, ArcherDX, AstraZeneca, AXIS, Beigene, BergenBio, Blueprint Medicines, Chugai Pharmaceutical, EMD Serono, Entos, EPG Health, Equity Treeline Bio, Exelixis, Harborside Nexus, Helsinn, Hengrui Therapeutics, i3 Health, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, mBrace, Medendi, Merus, Monopteros, MORE Health, MonteRosa, 14ner/Elevation Oncology, Novartis, Nuvalent, Ology, Pfizer, Prelude Inc., Remedica Ltd, Repare RX, RV More, Takeda/Ariad/Millenium, TouchIME, TP Therapeutics, Treeline Bio, Tyra Biosciences and Verastem; receives royalties from Wolters Kluwer; receives CME honoraria from Axis, Answers in CME, Clinical Care Options, EPG Health, Imedex, JNCC/Harborside, Liberum, Med Learning, Medscape, MJH Life Sciences, OncLive, Paradigm Medical Communications, Peerview Institute, PeerVoice, Physicians Education Resources, Remedica Ltd, Research to Practice, Targeted Oncology & WebMD; receives institutional research funding from Exelixis, GlaxoSmithKlein, Pfizer, PharmaMar, Taiho and Teva; receives other support from Boehringer Ingelheim; Merck, Merus & Puma; and is listed on a copyright application relating to the use of selpercatinib–osimertinib.

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Harada, G., Yang, SR., Cocco, E. et al. Rare molecular subtypes of lung cancer. Nat Rev Clin Oncol 20, 229–249 (2023). https://doi.org/10.1038/s41571-023-00733-6

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