Exploring dysfunctional pathways, mechanisms, and biomarkers in lung cancers
to discover new insights into the progression of the disease.


of the total number of cancer-related deaths worldwide are caused by lung cancer1


Lung cancer is the leading cause of cancer death in the United States2


5-year survival rate of lung cancer lung and bronchus cancer from diagnosis in the United States3


Lung cancer (including tracheal and bronchus cancers) is the leading cause of overall cancer-related mortality throughout the world, accounting for 18.0% of the total number of cancer-related deaths.1 In the United States, lung cancer has the second-highest incidence of all cancers in both men and women.4

There are two main categories of lung cancer: non-small cell lung cancer(NSCLC) and small cell lung cancer(SCLC).3


NSCLC is the most frequently occurring histologic subtype of lung cancer and accounts for >85% of all lung cancers.5-7 NSCLC can be further categorized into squamous (SQ) cell carcinoma and non-squamous (NSQ) NSCLC, which includes adenocarcinoma, defined by the type of cancerous cells and the unique growth and spread of the malignancy: 2,8-10, 39

  • Adenocarcinoma: Cancer that begins in the cells that line the alveoli and make substances such as mucus, represents ~40-50% of NSCLC 
  • Squamous cell carcinoma (also called epidermoid carcinoma), represents ~25%-30% of NSCLC
  • Large cell (undifferentiated) carcinoma: Cancer that may begin in several types of large cells, represents ~5-10% of NSCLC
  • Other less common subtypes of NSCLC: adenosquamous carcinoma, sarcomatoid carcinoma, neuroendocrine tumors

Mechanism of Disease

Squamous NSCLC arise centrally in thin, flat squamous cells within the large bronchi and are usually associated with smoking.10

Non-squamous NSCLC:1

  • Adenocarcinomas arise in the peripheral epithelial tissue and primarily have a lepidic, acinar, papillary, or mucinous morphology.8 Approximately 75% of adenocarcinomas are associated with smoking.10
  • Large cell carcinomas lack morphologic or immunohistochemistry evidence of clear lineage.2,8
  • Adenosquamous carcinomas are tumors with mixed adenocarcinoma and squamous cell carcinoma components, each being at least 10% of the tumor.2,8

Development involves a multistep process that includes multiple genetic and epigenetic alterations, particularly activation of growth-promoting pathways and inhibition of tumor-suppressing pathways.2,11-13

  • The most common targetable genomic alterations in lung adenocarcinoma are KRAS- and EGFR-activating mutations followed by ALK and ROS1 rearrangements, BRAF mutations, MET exon 14 skipping mutations and MET amplifications, RET gene fusions, and HER2 mutations. NTRK and NRG1 gene fusions rarely occur in NSCLC.40

Dysregulation of DNA repair is also associated with platinum resistance in NSCLC.14,15

  • Significantly correlates with the relative risk of death in patients with NSCLC who are treated with chemotherapy

Diagnosis & Staging

All NSCLC should be classified into specific pathologic subtypes based on the specific histologic and genetic characteristics of the patient's tumor using the 2015 WHO Guidelines.8 In the era of personalized medicine and targeted therapies, this can determine eligibility for certain types of molecular testing and therapeutic strategies.8 International guidelines recommend testing patients with NSCLC for select immune and molecular biomarkers (genomic alterations) that may have a predictive or prognostic value.2,39, 40

Challenges in Treatment

Most patients (>65%) present with Stage III or IV disease at diagnosis,16 which is a strong predictor of poor prognosis, with 5-year survival rates of 36% for Stage IIIA, ≤26% for Stages IIIB/IIIC, and ≤10% for Stage IV. 17

  • Advanced lung cancer patients typically have poor performance status at diagnosis and cannot tolerate aggressive chemotherapy.18
  • Choice of treatment is often driven by biomarkers associated with the patient's specific tumor biology.

Squamous and non-squamous histologies may react differently to similar therapies.

Some therapies may have different safety profiles and clinical outcomes depending on the histologic subtype of NSCLC present.

Predicting who will respond to immunotherapy targeting PD-1 and PD-L1 has proven to be difficult, and there remains a need to discover new predictive immunotherapy biomarkers.2

At least one third of patients with NSCLC have genomic alterations that will influence treatment selection. These patients should receive first-line therapy targeting the oncogene such as EGFR tyrosine kinase inhibitors (TKIs), ALK inhibitors, ROS1 inhibitors, BRAF inhibitors, KRAS inhibitors, and MET kinase inhibitors.2,39

In patients with no known actionable mutations, single-agent immunotherapy is recommended as first-line therapy, if PD-L1 expression is high (≥50%).2,39 For those with low (<50%) or negative (<1%) levels of PD-L1 expression, immunotherapy plus chemotherapy or chemotherapy alone are recommended.2,41

For these patients that do not harbor a targetable biomarker, strategies to improve the efficacy of chemotherapy is an unmet need.32,35 Combination therapies also hold promise to address the unmet need of treatment for patients unfit or resistant/refractory to current treatment options for NSCLC.36

Relevant Cancer Targets:


Learn about c-Met and its role in proliferation, cell survival, migration and invasivenessMORE>


Learn about SEZ6 and its expression in SCLCMORE>


Learn about CCR8 and T regulatory cellsMORE>

  1. Global Burden of Disease Cancer Collaboration; Sung H; Ferlay J, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J. Clin. 2021;71(3):209-249.
  2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.5.2019. ©2019 National Comprehensive Cancer Network, Inc. All rights reserved. To view the most recent and complete version of the NCCN Guidelines, go online to
  3. Cancer Stat Facts: Lung and Bronchus Cancer. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. Updated April 2018. Accessed September 2021.
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.
  5. Ardizzoni A, Boni L, Tiseo M, et al. Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst. 2007;99:847-857.
  6. Cheng H, Zhang Z, Borczuk A, et al. PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells. Carcinogenesis. 2013;34(4):739-749.
  7. Brahmer JR, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). Journal for ImmunoTherapy of Cancer. (2018) 6:75.
  8. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243-1260.
  9. Cetin K, Ettinger ES, Hei Y, O'Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol. 2011;3:139-148.
  10. Pandiri A. Comparative pathobiology of environmentally induced lung cancers in humans and rodents. Toxicol Pathol. 2015;43(1):107-114.
  11. Stead LF, Egan P, Devery A, et al. An integrated inspection of the somatic mutations in a lung squamous cell carcinoma using next-generation sequencing. PLoS One. 2013;8(11):1-8.
  12. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-525.
  13. Heist RS, Sequist LV, Engelman JA. Genetic changes in squamous cell lung cancer: a review. J Thorac Oncol. 2012;7(5):924-933.
  14. Bosken CH, Wei Q, Amos CI, Spitz MR. An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst. 2002;94(14):1091-1099.
  15. Zeng-Rong N, Paterson J, Alpert L, et al. Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res. 1995;55:4760-4764.
  16. Casal-Mourino A, Ruano-Ravina A, Lorenzo-Gonzalez M, et al. Epidemiology of stage III lung cancer: frequency, diagnostic characteristics, and survival. Transl Lung Cancer Res 2021; 10: 506-18.
  17. Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: Proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol 2016; 11: 39-51.
  18. Lwin Z, Weirss JR, Gandara D. The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era. J Thorac Dis. 2013;5(S5):S556-S564.
  19. Koinis F, Kotsakis A, Georgoulias V. Small cell lung cancer (SCLC): no treatment advances in recent years. Transl Lung Cancer Res. 2016;5(1):39-50.
  20. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas. 2010;39(6):707-712.
  21. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2012. National Cancer Institute. Bethesda, MD,, based on November 2014 SEER data submission, posted to the SEER website, April 2015.
  22. Karachaliou N, Pilotto S, Lazzari C, Bria E, de Marinis F, Rosell R. Cellular and molecular biology of small cell lung cancer: an overview. Transl Lung Cancer Res. 2016;5(1):2-15.
  23. Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5-21.
  24. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-1558.
  25. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53.
  26. Kalemkerian GP, Gadgeel SM. Modern staging of small cell lung cancer. J Natl Compr Canc Netw. 2013;11(1):99-104.
  27. Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 2015;121(5):664-672.
  28. van Meerbeeck JP, Fennell DA, De Ruysscher DKM. Small-cell lung cancer. Lancet. 2011;378:1741-1755.
  29. Pietanza MC, Byers LA, Minna JD, Rudin CM. Small cell lung cancer: will recent progress lead to improved outcomes? Clin Cancer Res. 2015;21(10):2244-2255.
  30. Alvarado-Luna G, Morales-Espinosa D. Treatment for small cell lung cancer, where are we now? A review. Transl Lung Cancer Res. 2016;5(1):26-38.
  31. Codony-Servat J, Verlicchi A, Rosell R. Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res. 2016;5(1):16-25.
  32. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998-2006.
  33. Codony-Servat J, Rosell R. Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res. 2015;4(6):689-703.
  34. Valent P, Bonnet D, De Maria R, et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer. 2012;12(11):767-775.
  35. Ramalingam SS, et al. Randomized, Placebo-Controlled, Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non–Small Cell Lung Cancer. Clin Cancer Res. 2017;23(8).
  36. Zhang et al. Emerging therapies for non-small cell lung cancer. Journal of Hematology & Oncology. (2019) 12:45.
  37. Liu SV, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630.
  38. Yang et al. Emerging therapies for small cell lung cancer. Journal of Hematology & Oncology. (2019) 12:47.
  39. Zappa C, et al. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res. 2016 Jun; 5(3): 288–300.
  40. Hendriks LE, Kerr KM, Menis J, et al. Oncogene addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023; 34: 339-57.
  41. Kerr KM, Bibeau F, Thunnissen E, et al. The evolving landscape of biomarker testing for non-small cell lung cancer in Europe. Lung Cancer 2021; 154: 161-75.
  42. Hendriks LE, Kerr KM, Menis J, et al. Non-oncogene addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 2023; 34: 358-76.