Lung Cancer

Depending on the tissue in which it is located, lung cancer is characterized as one of two types: non-small cell lung cancer (NSCLC), which is the most prevalent and accounts for 85% of cases, and small cell lung cancer (SCLC), which accounts for the remaining 15%. NSCLC forms within lung epithelial tissue and has three major subtypes: adenocarcinoma (LDAC), squamous cell carcinoma and large cell carcinoma. SCLC forms within neuroendocrine tissues and, although it is less common than NSCLC, it can spread quickly. Immunohistochemistry is used clinically to identify and determine the stage of the tumor and the possible treatment options.

Lung Cancer Metastasis

Some cancers, including breast and colon cancers, metastasize to the lung at a high frequency. The mechanisms driving these metastases are therefore important in lung cancer research. The tumor microenvironment (TME) has a strong influence on the metastatic potential of a tumor. The hypoxic TME of breast cancer tumors induces the expression of lysyl oxidase, via HIF-1α, which can promote metastasis to the lung by increasing collagen crosslinks and adhesion. Inhibition of HIF-1α using LW 6 (Cat. No. 6322) or activation of HIF1α using ML 228 (Cat. No. 4565) can therefore be used to study the transcriptional changes that occur in breast cancer that may lead to metastasis and adhesion to the lung.

Immuno-oncology and the Tumor Microenvironment

The TME affects metastasis and oncogenesis; it is also a key contributor to the immunosuppressive nature of lung cancer, particularly in NSCLC. By suppressing the immune system within the TME, a tumor is more likely to evade detection. Combining this with the dysregulation or loss of tumor suppressors further drives cancer growth.

Oncogene drivers are one useful research target. For example, PTEN acts as a tumor suppressor gene. It is a phosphatase that regulates the cell cycle to prevent cells from dividing and growing too rapidly, and the loss of PTEN contributes to the immunosuppressive TME. PTEN inhibition using the PTEN inhibitor SF 1670 (Cat. No. 5020) can be used to understand the mechanisms contributing to the development and maintenance of an immunosuppressive TME.

Lung Cancer Driver Genes

The lung cancer subtypes, with their specific vulnerabilities and dependencies, have been characterized through single cell work, but can now be examined in greater detail via genomic and proteomic studies. Both the tumor itself and the TME display heterogeneity, with different subtypes of cells associated with different types of lung cancer. There is extensive interplay between lung cancer cells and the surrounding TME and these interactions influence invasion, metastasis and tumor growth. They also affect how well a tumor will respond to treatment and whether treatment resistance will develop.

Various driver genes associated with lung cancer are lost or upregulated during disease progression. The loss of tumor suppressors such as TP53, cyclin dependent kinase inhibitor 2A (CDKN2A), PTEN and NF1, and the upregulation of oncogenes including KRAS, EGFR, BRAF, MET or RET are all significant to lung cancer, and mutations in KRAS or EGFR are considered initiating events directing tumor clonal evolution and progression. Oncogenic fusions, the formation of a gene from the fusion of two genes, can produce more abnormal protein than non-fusion genes and promote tumor growth. Oncogenic fusions have been reported with ALK, ROS1 and RET (some of the reported oncogenic fusions are summarized in Table 1), these fusions can be targeted with tyrosine kinase inhibitors or with compounds such as XL 184 (Cat. No. 5422).

Table 1. Table showing some of the oncogenic fusions reported in lung cancer tumors and their occurrence in non-small cell lung cancer.

Cancer-Associated Fibroblasts

Cancer associated fibroblasts (CAFs) are cells within the TME that promote tumor growth by secreting cytokines or inducing changes in the extracellular matrix. CAFs express the IGF2 ligand which increases NANOG expression and subsequently increases stem cell enrichment via IGFR1R. Pharmacological inhibition of IGF1R, using an inhibitor such as NVP ADW 742 (Cat. No. 5247), could help define the role of cancer stem cells within lung cancer and can be combined with markers to monitor cancer stem cell population changes.

CAFs not only influence the TME, they are also potent regulators of angiogenesis and may help us understand the process of tumor growth and metastasis. VEGFR has an essential role in angiogenesis and in lung cancer growth, invasion and interaction with the TME. By inhibiting angiogenesis using VEGFR inhibitors, such as Cediranib (Cat. No. 7454), Vandetanib (Cat. No. 7497) and Bevacizumab (R&D Systems, Cat. No. MAB9947) the cellular mechanisms involved in this key process could be further defined.

Lung Cancer Organoids

The wide genetic variation within specific lung cancer tumors indicates the need for more individualized treatments. It is possible to grow tissue derived directly from a patient's tumor cells, either by culturing cells or by producing lung organoids. The cells or organoids can be tested in vitro to determine how the tumor is likely to respond to various treatments; the treatments with the best outcomes can then be applied to treat the tumor and patient.

Conventional application of chemotherapy-based tools including 5-Fluorouracil (Cat. No. 3257) and orally available prodrugs such as Capecitabine (Cat. No. 4799) can be used alongside lung organoids to reproduce a clinical treatment background to monitor the evolution of treatment resistance. Organoids and in vivo approaches can also be combined with pharmacologically-induced antitumor immunity, for example by using checkpoint inhibitors like Lin28 1632 (Cat. No. 6068) to reduce PD-L1 expression. Immuno-oncology can also be used to further characterize the immune response. The interactions between the tumor and the TME are clearly complex, and compound libraries may offer an approach to further understand this relationship and reveal new pathways of interest.

Related Resources From Our Sister Brands

In addition to the more traditional histology techniques, the application of in situ hybridization approaches such as RNAscope^TM and BaseScope provide additional techniques for identifying mutations or transcriptional changes in the early stages of lung cancer. These changes can help identify vulnerabilities and treatment options. Studying specific gene mutations that cause cell death when combined with one or more other specific mutations, called synthetic lethality, provides another avenue for research. For example, a targeted protein degradation approach can be used to target KRAS mutants with the LC 2 PROTAC^® (Cat. No. 7420) along with VEGFR inhibitor BMS 605541 (Cat. No. 6069) to determine the effect on TME changes. Alternatively mutant specific inhibitors of EGFR such as EMI 48 (Cat. No. 7424) can be used to target specific subsets of a tumor population. These can all be used in combination with RNAscope^TM to understand transcriptional changes and tumor adaptations to find new targets of interest.

PROTAC^® is a registered trademark of Arvinas Operations, Inc., and is used under license.

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