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Understanding and targeting resistance mechanisms in NSCLC

Key Points

  • The spectrum of known and putative oncogenic drivers with companion targeted therapies continues to increase. As broader mutational testing becomes more clinically available, a greater proportion of patients with non-small-cell lung cancer (NSCLC) will be eligible for targeted therapies.

  • Mechanisms of resistance to targeted therapies can be divided into 'on-target' alterations in the primary drug target and 'off-target' changes that influence downstream and parallel bypass signalling pathways.

  • There is both signalling crosstalk and overlap among downstream and bypass signalling pathways that lead to resistance to the different targeted therapies currently in clinical use for treating NSCLC, suggesting that common themes in the development of drug resistance can be leveraged to guide further development of therapeutic agents and strategies.

  • The upfront combination of therapies targeting both the oncogenic driver and common bypass pathways might delay the onset of disease progression in NSCLC and is the subject of ongoing clinical trials.

  • Bidirectional signalling between tumour cells and components of the tumour microenvironment (TME) shapes both the characteristics of the TME and the propensity of a tumour cell towards therapeutic resistance.

  • Tissue biopsy at disease progression might identify modes of therapeutic resistance to guide the rational selection of subsequent lines of therapy. Serial assessment of circulating tumour DNA might provide a complementary approach to capture heterogeneous and evolving resistance mechanisms in patients.

Abstract

The expanding spectrum of both established and candidate oncogenic driver mutations identified in non-small-cell lung cancer (NSCLC), coupled with the increasing number of clinically available signal transduction pathway inhibitors targeting these driver mutations, offers a tremendous opportunity to enhance patient outcomes. Despite these molecular advances, advanced-stage NSCLC remains largely incurable due to therapeutic resistance. In this Review, we discuss alterations in the targeted oncogene ('on-target' resistance) and in other downstream and parallel pathways ('off-target' resistance) leading to resistance to targeted therapies in NSCLC, and we provide an overview of the current understanding of the bidirectional interactions with the tumour microenvironment that promote therapeutic resistance. We highlight common mechanistic themes underpinning resistance to targeted therapies that are shared by NSCLC subtypes, including those with oncogenic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1), serine/threonine-protein kinase b-raf (BRAF) and other less established oncoproteins. Finally, we discuss how understanding these themes can inform therapeutic strategies, including combination therapy approaches, and overcome the challenge of tumour heterogeneity.

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Figure 1: Milestones in targeted therapy for NSCLC.
Figure 2: Signalling pathways driving resistance to EGFR TKIs in NSCLC.
Figure 3: Signalling pathways in resistance to ALK and ROS1 TKIs in NSCLC.
Figure 4: Other oncogenic drivers in NSCLC.
Figure 5: The tumour microenvironment and resistance to targeted inhibitors.

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Author information

Affiliations

Authors

Contributions

J.R. researched data for the article. Both authors contributed equally to the discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Trever G. Bivona.

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Competing interests

T.G.B. declares that he is a co-founder of Driver; a consultant for Novartis, AstraZeneca, Ariad and Teva; a member of the scientific advisory board for Array Biopharma and Revolution Medicines; and supported by Ignyta and Revolution Medicines for research funding. J.R. declares a relationship with Revolution Medicines as a consultant.

PowerPoint slides

Glossary

Intrinsic resistance

Tumour cell resistance to therapy due to baseline characteristics present before therapy exposure.

Adaptive resistance

Dynamic changes in tumour cell signalling occurring during treatment with targeted therapy that promote therapy resistance.

Acquired resistance

New molecular alterations leading to the development of targeted therapy resistance after an initial period of drug sensitivity.

Tyrosine kinase inhibitors

A class of small-molecule inhibitors that antagonize receptor tyrosine kinase signalling.

Non-covalent inhibitors

Inhibitors that bind to a target protein in a non-covalent, reversible manner.

Covalent inhibitor

An inhibitor that binds to a target protein via irreversible, covalent bonds.

Synthetic lethality

Induction of tumour cell death upon simultaneous inhibition of two signalling pathways, the individual loss of which does not lead to cell death.

Activation loop

A structural component of receptor tyrosine kinases that is important for the regulation of catalytic activity.

Steric hindrance

Interference with protein binding due to physical interference related to protein structure.

Type I TKI

ATP-competitive small-molecule TKIs that bind at the ATP binding site while in the active kinase conformation.

Type II TKIs

Small-molecule TKIs that bind at and near the ATP binding site in the inactive kinase conformation.

Sarcomatoid carcinoma

Pulmonary sarcomatoid carcinoma is an uncommon and aggressive poorly differentiated form of NSCLC.

Intratumoural heterogeneity

Variation in tumour cell genomic and phenotypic characteristics within a given tumour.

Convergent evolution

The independent development of alterations within the same signalling pathways among different tumour cell clones during the course of tumour cell evolution.

Radiographic progression

Tumour enlargement and/or new lesion development that are visible on radiographic studies and meet specific criteria.

Residual disease

Persistent tumour burden despite disease stabilization and/or an objective response to antineoplastic therapy.

Oligoprogressive disease

Isolated growth of malignant lesions despite continued control of overall tumour disease burden.

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Rotow, J., Bivona, T. Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer 17, 637–658 (2017). https://doi.org/10.1038/nrc.2017.84

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