Targetable Driver Mutations Research Articles

Inhibition of TWIST1 Leads to Activation of Oncogene-Induced Senescence in Oncogene-Driven Non–Small Cell Lung Cancer

A large fraction of non-small cell lung cancers (NSCLC) are dependent on defined oncogenic driver mutations. Although targeted agents exist for EGFR- and EML4-ALK-driven NSCLCs, no therapies target the most frequently found driver mutation, KRAS. Furthermore, acquired resistance to the currently targetable driver mutations is nearly universally observed. Clearly a novel therapeutic approach is needed to target oncogene-driven NSCLCs. We recently showed that the basic helix-loop-helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to Kras-induced senescence. In the current study, we examine the role of TWIST1 in oncogene-driven human NSCLCs. Silencing of TWIST1 in KRAS-mutant human NSCLC cell lines resulted in dramatic growth inhibition and either activation of a latent oncogene-induced senescence program or, in some cases, apoptosis. Similar effects were observed in EGFR mutation-driven and c-Met-amplified NSCLC cell lines. Growth inhibition by silencing of TWIST1 was independent of p53 or p16 mutational status and did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. In xenograft models, silencing of TWIST1 resulted in significant growth inhibition of KRAS-mutant, EGFR-mutant, and c-Met-amplified NSCLCs. Remarkably, inducible silencing of TWIST1 resulted in significant growth inhibition of established KRAS-mutant tumors. Together these findings suggest that silencing of TWIST1 in oncogene driver-dependent NSCLCs represents a novel and promising therapeutic strategy.

Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large-cell carcinoma

Pulmonary large-cell carcinoma—a diagnostically and clinically controversial entity—is defined as a non-small-cell carcinoma lacking morphologic differentiation of either adenocarcinoma or squamous cell carcinoma, but suspected to represent an end stage of poor differentiation of these tumor types. Given the recent advances in immunohistochemistry to distinguish adenocarcinoma and squamous cell carcinoma, and the recent insights that several therapeutically relevant genetic alterations are distributed differentially in these tumors, we hypothesized that immunophenotyping may stratify large-cell carcinomas into subsets with distinct profiles of targetable driver mutations. We therefore analyzed 102 large-cell carcinomas by immunohistochemistry for TTF-1 and ΔNp63/p40 as classifiers for adenocarcinoma and squamous cell carcinoma, respectively, and correlated the resulting subtypes with nine therapeutically relevant genetic alterations characteristic of adenocarcinoma (EGFR, KRAS, BRAF, MAP2K1/MEK1, NRAS, ERBB2/HER2 mutations and ALK rearrangements) or more common in squamous cell carcinoma (PIK3CA and AKT1 mutations). The immunomarkers classified large-cell carcinomas as variants of adenocarcinoma (n=62; 60%), squamous cell carcinoma (n=20; 20%) or marker-null (n=20; 20%). Genetic alterations were found in 38 cases (37%), including EGFR (n=1), KRAS (n=30), BRAF (n=2), MAP2K1 (n=1), ALK (n=3) and PIK3CA (n=1). All molecular alterations characteristic of adenocarcinoma occurred in tumors with immunoprofiles of adenocarcinoma or marker-null, but not in tumors with squamous immunoprofiles (combined mutation rate 50% vs 30% vs 0%, respectively; P<0.001), whereas the sole PIK3CA mutation occurred in a tumor with squamous profile (5%). Furthermore, marker-null large-cell carcinomas were associated with significantly inferior disease-free (P<0.001) and overall (P=0.001) survival. In conclusion, the majority (80%) of large-cell carcinomas can be classified by immunomarkers as variants of adenocarcinoma or squamous cell carcinoma, which stratifies these tumors into subsets with a distinct distribution of driver mutations and distinct prognoses. These findings have practical implications for diagnosis, predictive molecular testing and therapy selection.

Driver Mutations in Melanoma: Lessons Learned From Bench-to-Bedside Studies

The identification of somatic driver mutations in human samples has allowed for the development of a molecular classification for melanoma. Recent breakthroughs in the treatment of metastatic melanoma have arisen as a result of these significant new insights into the molecular biology of the disease, particularly the development of inhibitors of activating BRAF(V600E) mutations. In this article the roles of several mutations known to be involved in the malignant transformation of melanocytes are reviewed including BRAF, PTEN, NRAS, ckit, and p16 as well as some of the emerging mutations in cutaneous and uveal melanoma. The bench to bedside collaborations that resulted in these discoveries are summarized, and potential therapeutic strategies to target driver mutations in specific patient subsets are discussed.

Treatment of Chronic Myelogenous Leukemia as a Paradigm for Solid Tumors: How Targeted Agents in Newly Diagnosed Disease Transformed Outcomes

Although chronic myelogenous leukemia (CML) is rare, with approximately 5000 new cases in the United States annually, it may be the poster child for the future of oncology. Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor (TKI), transformed the course of CML from a rapidly fatal disease (median survival, 3 to 6 years) to a functionally curable, indolent disease with an estimated median survival of more than 25 years. This transformation can be attributed to several key factors: the identification of a causal and actionable molecular aberration-BCR-ABL; the development of a potent and selective Bcr-Abl TKI-imatinib; and, importantly the application of imatinib in the earliest phase of CML. In contrast, imatinib, if used in CML blastic phase, improves median survival to only about 1 year. Similar to CML blastic phase, metastatic solid malignancies have undergone genetic evolution, and their molecular aberrations are complex. As a result, resistance is common and eradication is difficult. The key to the dramatic improvement in the survival of patients with CML involved using imatinib in newly diagnosed disease, before blastic transformation. We hypothesize that metastatic solid tumors are analogous to CML blastic phase, and that to achieve improvements in solid tumor outcomes similar to those seen in CML, application of targeted agents to newly diagnosed disease may be required to prevent disease transformation (i.e., metastases). Targeting driver mutations at the time of diagnosis may be critical to the goal of markedly changing the outlook for patients with cancer.