Historically lung cancer, like many cancers, was treated as a homogenous disease, with the mainstays of chemotherapy, radiotherapy and surgery. Physicians determined which of these therapies was most appropriate based on the staging or histology of disease. Staging refers to the process of dividing lung cancer into stages ranging from I- IV, based on how far the tumour has spread within or beyond the lungs. Histology, alternately, looked at classifying tumours as small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), based upon the microscopic appearance of cells.
However, since 2004, researchers have looked to molecular subtyping.1 Some tumours can be grouped by the presence of actionable driver mutations, genetic alterations, and/or protein over-expression in lung cancer cells. The presence of these biological molecules (known as biomarkers) can serve as indicators of various types of cancer. Up to half of NSCLC cases are associated with point mutations.2
Molecular subtyping in particular has led to significant advances in cancer treatments, shedding light on specific molecular changes during the development and progression of cancer. Over the last few decades, research has discovered over a dozen different point mutations or molecular alterations that may contribute to the growth of NSCLC tumours.2 Exploiting the specific point mutation within a gene may help us find new ways to target NSCLC tumours.
The identification of gene mutations is the basis for precision medicine, which allows physicians to match patients with targeted therapies specifically designed for their disease. For patients whose tumours harbor ALK, EGFR, BRAF and ROS1 gene mutations, researchers have been able to develop targeted therapies that are designed to specifically address these mutations driving tumour growth.3 Targeted therapies are defined as a type of treatment that identifies and attacks specific types of cancer cells, while aiming to spare normal, non-cancerous, cells. As a result of this selective action, targeted therapies are often associated with improved survival with reduced side effects.4
In the creation of these targeted therapies, researchers were able to identify some of the factors required for tumour development and growth, and so developed drugs to directly bind to and disrupt these factors. For example, some therapies may block the action of certain enzymes, proteins or other molecules involved in tumour cell proliferation, causing the tumour to shrink significantly.3
One such class of therapies target the epidermal growth factor receptor (EGFR), a protein on the surface of cells that may encourage NSCLC cells to grow or proliferate faster. Specific drugs called EGFR tyrosine kinase inhibitors (TKIs) can block the signal from the EGFR that tells the cells to grow or multiply.5,6
The Emergence of Resistance Mechanisms
In many patients, their initial treatment eventually stops working due to acquired resistance.
How resistance emerges in a tumor remains unclear, although there are several hypotheses7:
1. Due to the heterogeneity within a tumour, certain resistance mechanisms exist in some of the tumour cells prior to treatment. While the susceptible tumour cells will die off, the resistant cells multiply, forming a new, resistant tumour
2. The treatment itself induces a drug-tolerant population of cells because of mutations that occur during the continued replication of genetically-varied tumour cells
3. Targeting of the genetic mutation itself induces epigenetic or genetic changes, leading to resistance
Researchers are investigating the potential for new treatment strategies to address resistance mutations when they appear, in the hopes of further extending survival and staying one step ahead of the continually evolving disease.
Cancer is continuously evolving and so must our treatment strategies, both through the development of new molecules and through the discovery of optimised treatment sequences and potentially synergistic combinations.
AstraZeneca is committed to exploring the mechanisms that stimulate acquired resistance and understanding the best ways to target them. Lung cancer remains the leading cause of cancer-related death, and for many patients there are still limited treatment options to offer improved outcomes. Understanding and clarifying the biology of resistance in NSCLC has already resulted in the development of new therapies and treatment strategies, and has the potential to guide future drug development, with the goal of getting and staying a step ahead of cancer.
1. Politi K &Herbst RS. Lung Cancer in the Era of Precision Medicine. Clin Cancer Res. 2015;21(10):2213–20.
2. Korpanty G, et al. Biomarkers that currently affect clinical practice in lung cancer: EGFR, ALK, MET, ROS-1, and KRAS. Frontiers in Oncology. 2014(4).
3. American Cancer Society. Targeted Therapy Drugs for Non-Small Cell Lung Cancer. Available at
https://www.cancer.org/cancer/non-small-cell-lung-cancer/treating/targeted-therapies.html. Accessed September 2018.
4. National Cancer Institute Dictionary of Cancer Terms: Targeted Therapy. Available at https://www.cancer.gov/publications/dictionaries/cancer-terms/def/targeted-therapy. Accessed September 2018.
5. NIH Genetics Home Reference: EGFR gene. Available at https://ghr.nlm.nih.gov/gene/EGFR. Accessed September 2018.
6. Bethune G, et al. Epidermal Growth Factor Receptor (EGFR) in Lung Cancer: An Overview and Update. J Thorac Dis. 2010;2(1):48-51.
7. Neel DS & Bivona TG. Resistance is Futile: Overcoming Resistance to Targeted Therapies in Lung Adenocarcinoma. npj Precision Oncology. 2017:1;3.
Veeva ID: Z4-13246
Date of prep: 12/10/2018
Date of expiry: 12/10/2020