Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of “client” proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.

Lung cancer is the deadliest malignancy with more cancer deaths per year than the next three cancers combined. Despite remarkable advances in targeted therapy, advanced lung cancer patients have not experienced a significant improvement in mortality. Lung cancer has been shown to be immunogenic and responsive to checkpoint blockade therapy. Checkpoint signals such as CTLA-4 and PD-1/PD-L1 dampen T cell activation and allow tumors to escape the adaptive immune response. Response rates in patients with pretreated, advanced NSCLC were much higher and more durable with PD-1 blockade therapy compared to standard-of-care, cytotoxic chemotherapy. Therefore, PD-1 inhibitors such as nivolumab and pembrolizumab were rapidly approved for both squamous and nonsquamous lung cancer in the pretreated population. The advent of these new therapies have revolutionized the treatment of lung cancer; however, the majority of NSCLC patients still do not respond to PD-1/PD-L1 inhibition leaving an unmet need for a large and growing population. Immunotherapy combinations with chemotherapy, radiation therapy, or novel immunomodulatory agents are currently being examined with the hope of achieving higher response rates and improving overall survival rate. Chemotherapy and radiation therapy has been theorized to increase the release of tumor antigen leading to increased responses with immunotherapy. However, cytotoxic chemotherapy and radiation therapy may also destroy actively proliferating T cells. The correct combination and order of therapy is under investigation. The majority of patients who do respond to immunotherapy have a durable response attributed to the effect of adaptive immune system’s memory. Unfortunately, some patients’ tumors do progress afterward and investigation of checkpoint blockade resistance is still nascent. This review will summarize the latest efficacy and safety data for early and advanced NSCLC in both the treatment-naïve and pretreated settings. The emerging role of immunotherapy for the treatment of small cell lung cancer and malignant mesothelioma will also be discussed.

TWIST1, an epithelial–mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non–small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical–bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of TWIST1 by inducing oncogene-induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC. Implications: TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. Mol Cancer Res; 15(12); 1764–76. ©2017 AACR.

Lung Cancer is occasionally observed in patients with Idiopathic Pulmonary Fibrosis (IPF). We sought to describe the epidemiologic and clinical characteristics of lung cancer for patients with IPF and other interstitial lung disease (ILD) using institutional and statewide data registries. We conducted a retrospective analysis of IPF and non-IPF ILD patients from the ILD center registry, to compare with lung cancer registries at the University of Pittsburgh as well as with population data of lung cancer obtained from Pennsylvania Department of Health between 2000 and 2015. Among 1108 IPF patients, 31 patients were identified with IPF and lung cancer. The age-adjusted standard incidence ratio of lung cancer was 3.34 (with IPF) and 2.3 (with non-IPF ILD) (between-group Hazard ratio = 1.4, p = 0.3). Lung cancer worsened the mortality of IPF (p < 0.001). Lung cancer with IPF had higher mortality compared to lung cancer in non-IPF ILD (Hazard ratio = 6.2, p = 0.001). Lung cancer among IPF was characterized by a predilection for lower lobes (63% vs. 26% in non-IPF lung cancer, p < 0.001) and by squamous cell histology (41% vs. 29%, p = 0.07). Increased incidence of lung cancer was observed among single lung transplant (SLT) recipients for IPF (13 out of 97, 13.4%), with increased mortality compared to SLT for IPF without lung cancer (p = 0.028) during observational period. Lung cancer is approximately 3.34 times more frequently diagnosed in IPF patients compared to general population, and associated with worse prognosis compared with IPF without lung cancer, with squamous cell carcinoma and lower lobe predilection. The causality between non-smoking IPF patients and lung cancer is to be determined.