The discovery that some lung cancers harbor specific somatic 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, and the discovery that antitumor T cell responses are regulated by immune checkpoints, have paved the way for molecularly targeted, personalized lung cancer therapy. Lung cancer is classified based on histologic features as either non–small-cell lung cancer (NSCLC; approximately 85% of all lung cancers) or small-cell lung cancer (SCLC; approximately 15%).1 NSCLCs are further divided histologically as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Various chemotherapeutic regimens have been used to treat different NSCLC histologic subtypes. But with the realization that NSCLC is a collection of diseases that are identifiable by specific molecular abnormalities, personalized therapy is achievable for a subset of patients with NSCLC (Fig. 107-1).
Driver mutations in lung adenocarcinoma.
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) with trastuzumab in breast cancer, are prime examples of successful therapeutic targeting of critical signaling nodes in cancer.
Between 1980 and 2000, NSCLC oncogenic drivers 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 tumor suppressor genes. 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.2–4 These EGFR driver mutations resulted in a receptor with dysregulated 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 EGFR’s tyrosine kinase (TK) function. In 2007, translocation of the echinoderm microtubule-associated protein-like 4 (EML4) translocation to the anaplastic lymphoma kinase (ALK) gene resulting in an EML4-ALK fusion gene5 and chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1)6 were identified in NSCLC. As with EGFR, the EML4-ALK translocation and ROS1 oncogenic fusion resulted in dysregulated TK signaling, again driving cell growth and the oncogenic phenotype, as well as cellular dependencies on EML4-ALK and ROS1 signaling, respectively. Targeting ALK and ROS1 with TKIs has been shown to be highly effective in NSCLCs that express ...