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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung

Giuseppe Lamberti1, Elisa Andrini1, Monia Sisi1

  • 1Department of Specialized, Experimental and Diagnostic Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Critical Reviews in Oncology/Hematology
|October 14, 2020
PubMed

Insights

Targeted therapies offer improved survival for non-small cell lung cancer (NSCLC) patients with specific genetic alterations. This review covers emerging treatments for KRAS, BRAF, MET, RET, HER2, and NTRK drivers and strategies to overcome resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Lung cancer remains a leading cause of cancer death globally.
  • Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1 tyrosine kinase inhibitors (TKIs) have significantly improved outcomes for oncogene-addicted non-small cell lung cancer (NSCLC) patients.
  • High-throughput sequencing has identified additional oncogenic drivers, including BRAF, MET, RET, HER2, and NTRK, along with KRAS.

Purpose of the Study:

  • To review the clinicopathological features of advanced NSCLCs driven by KRAS, BRAF, MET, RET, HER2, and NTRK.
  • To discuss emerging targeted therapies and their clinical development for these NSCLC subtypes.
  • To explore mechanisms of resistance to TKIs and strategies to overcome them.

Main Methods:

  • Literature review of clinical trials and research studies.
  • Analysis of clinicopathological data for NSCLC patients with specific driver mutations.
  • Synthesis of information on targeted therapies, resistance mechanisms, and overcoming resistance strategies.

Main Results:

  • Targeted therapies, including TKIs, have shown impressive activity and survival improvements for NSCLCs with identified genomic alterations.
  • Several novel drugs targeting previously difficult-to-treat drivers like KRAS are in clinical development, with some receiving accelerated FDA approval.
  • Acquired resistance to TKIs, through on-target or off-target mechanisms, is a significant clinical challenge.

Conclusions:

  • Emerging targeted therapies offer new hope for patients with advanced NSCLC harboring specific oncogenic drivers.
  • Understanding and overcoming resistance mechanisms are crucial for durable clinical benefit.
  • Further research into novel therapeutic strategies and combination approaches is warranted.
Keywords:
BRAFHER2KRASMETNTRKNext-generation sequencingNon-small cell lung cancerRET

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