Genetic and Molecular Changes in Lung Cancer: Prospects for a Personalized Pharmacological Approach to Treatment
Lung cancer is the most common cause of cancer-related death in men and women worldwide, responsible for over 1 million deaths annually.1 Each year, more people die of lung cancer than of the next three leading causes of cancer death combined: breast, colon, and prostate cancer. Despite advances in surgical techniques and combined therapies, lung cancer remains a disease with a dismal prognosis. Although 1-year survival has improved over the past few decades, overall 5-year survival has remained relatively unchanged at 12% to 16% over the past 30 years.2 These data underscore the need to develop new diagnostic modalities and therapeutic approaches to target lung cancer.
Lung cancer therapy is in the midst of a revolution toward personalized therapy. A key discovery in the past decade has been that some lung cancers harbor specific mutations that are essential for malignant growth (i.e., “driver mutations”), which lead to gain of function of oncogenes or loss of function of tumor suppressor genes (TSGs). In contrast, lung cancers also harbor mutations that are functionally insignificant (i.e., “passenger mutations”). While clearly promoting the oncogenic state, driver mutations are also commonly associated with “oncogene addiction,” or dependency of some cancers on one gene for the maintenance of the malignant phenotype. These dependencies, which are specific to an individual's cancer, are absent in normal cells. Inhibition of “druggable” proteins coded for by driver mutations, such as the BCR-ABL fusion protein with imatinib in chronic myelogenous leukemia or human epidermal growth factor receptor 2 (HER2)/Neu with trastuzumab in breast cancer, are prime examples of successful therapeutic targeting of critical signaling nodes in cancer.
Historically, nonsmall cell lung cancer (NSCLC) has been classified histologically as squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, and various chemotherapeutic regimens have been used to treat different histological subtypes. But with the realization that NSCLC is a collection of diseases that are identifiable by specific molecular abnormalities, personalized therapy became a goal – and now a reality – for patients with NSCLC. Between 1980 and 2000, NSCLC driver lesions that were investigated included mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) and protein 53 (p53) genes, loss of specific chromosomal loci, loss of heterozygosity, and DNA methylation of TSGs. In 2004, driver mutations in the epidermal growth factor receptor (EGFR) gene, a membrane-bound receptor tyrosine kinase (RTK) that regulates cell growth, were discovered in NSCLC, especially in adenocarcinomas.3–5 These EGFR driver mutations resulted in a receptor with deregulated signaling driving cell growth and the oncogenic phenotype, but also led to a cellular dependence on EGFR RTK signaling. Thus, these mutations were strongly associated with therapeutic sensitivity to tyrosine kinase inhibitor (TKI) drugs that inhibited the tyrosine kinase (TK) function of EGFR. In 2007, the existence of the echinoderm ...