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Review
. 2021 Mar 5;22(5):2625.
doi: 10.3390/ijms22052625.

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Sara Elena Rebuzzi  1   2 , Lodovica Zullo  3 , Giovanni Rossi  4   5 , Massimiliano Grassi  1 , Veronica Murianni  1 , Marco Tagliamento  2   3 , Arsela Prelaj  6   7 , Simona Coco  3 , Luca Longo  3 , Maria Giovanna Dal Bello  3 , Angela Alama  3 , Chiara Dellepiane  3 , Elisa Bennicelli  3 , Umberto Malapelle  8 , Carlo Genova  2   9
Affiliations
Review

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

Sara Elena Rebuzzi et al. Int J Mol Sci. .

Abstract

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal-epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

Keywords: HER2; KRAS; MET; NTRK; PIK3CA; RET; non-small cell lung cancer; targeted therapy.

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Conflict of interest statement

C.G. reports honoraria from AstraZeneca, Bristol-Myers-Squibb, Merck-Sharp-Dohme, Boehringer-Ingelheim and Roche, outside the submitted manuscript. M.T. declares travel grants from Roche, Bristol-Myers Squibb, AstraZeneca, Takeda and honoraria as medical writer from Novartis and Amgen, outside the submitted manuscript. G.R. reports honoraria from Bristol-Myers-Squibb, Roche, Amgen, Jansenn, outside the submitted manuscript. A.P. reports personal fees from Roche, AstraZeneca and BMS, outside the submitted work. U.M. reports personal fees (for service in the speaker bureau and as advisor) from Boehringer Ingelheim, AstraZeneca, Roche, MSD, Amgen, Merck, Eli Lilly, Thermofisher, Diaceutics. All remaining authors have declared no conflict of interest.

Figures

Figure 1
Figure 1
Molecular pathways of novel emerging targets in NSCLC and agents in clinical development. Several molecular pathways are physiologically activated by the interactions between circulating growth factors (colored circles) and trans-membrane receptors (colored sticks crossing the cell membrane), which result in the downstream activation of intracellular proteins (colored ovoids) associated with cell proliferation, increased aggressiveness, or immune escape. The details for each individual pathway are described in the appropriate paragraphs. Molecular alterations (e.g., gene fusions) potentially associated with tumorigenesis are reported next to the relevant molecule. When available, investigational agents able to inhibit specific pathways are reported (blank boxes), with reference to the specifically targeted molecule or interaction.
See this image and copyright information in PMC

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