PTEN in Lung Cancer: Dealing with the Problem, Building on New Knowledge and Turning the Game Around

Abstract

Lung cancer is the most common malignancy and cause of cancer deaths worldwide, owing to the dismal prognosis for most affected patients. Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) acts as a powerful tumor suppressor gene and even partial reduction of its levels increases cancer susceptibility. While the most validated anti-oncogenic duty of PTEN is the negative regulation of the PI3K/mTOR/Akt oncogenic signaling pathway, further tumor suppressor functions, such as chromosomal integrity and DNA repair have been reported. PTEN protein loss is a frequent event in lung cancer, but genetic alterations are not equally detected. It has been demonstrated that its expression is regulated at multiple genetic and epigenetic levels and deeper delineation of these mechanisms might provide fertile ground for upgrading lung cancer therapeutics. Today, PTEN expression is usually determined by immunohistochemistry and low protein levels have been associated with decreased survival in lung cancer. Moreover, available data involve PTEN mutations and loss of activity with resistance to targeted treatments and immunotherapy. This review discusses the current knowledge about PTEN status in lung cancer, highlighting the prevalence of its alterations in the disease, the regulatory mechanisms and the implications of PTEN on available treatment options.

Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient

“…The involvement of PTEN has been widely reported in lung cancer, although genetic alterations such as mutations and deletions are not the main recurring event, ranging from 2% to 7% of the cases [118]. Conversely, the loss of PTEN protein is more frequently observed, involving about 40% of lung cancer patients and showing a correlation with smoking history, squamous histotype and shorter survival [118]. Interestingly, PTEN loss of activity has also been linked to resistance to targeted treatments and to immunotherapy, as well.…”

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

“…PTEN altered function occurs in approximately 13.5% of human cancers through inframe, missense, and truncating mutations, gene fusions, amplifications, deletions, epigenetic silencing, and transcriptional modifications ( In particular, PTEN gene alterations are more frequent in endometrial cancer (35%), glial tumors (32%), prostate cancer (17%), melanoma (13%), non-small small-cell lung cancer (NSCLC) (12%), and breast cancer (9%) [63][64][65][66][67][68]. Of note, PTEN protein loss is a more frequent event in cancer, compared to PTEN genetic alterations, particularly in lung cancer and breast cancer [42,47,69]. Hence, only 9% of lung squamous cell carcinoma harbor PTEN somatic mutations, while up to 44% showed decreased protein levels [69].…”

“…Of note, PTEN protein loss is a more frequent event in cancer, compared to PTEN genetic alterations, particularly in lung cancer and breast cancer [42,47,69]. Hence, only 9% of lung squamous cell carcinoma harbor PTEN somatic mutations, while up to 44% showed decreased protein levels [69]. Similarly, PTEN protein loss or low expression occurs in 46% of invasive breast cancers, with particularly higher frequency in ductal and estrogen receptor (ER) POS /HER2 NEG breast cancers [47].…”

“…In particular, PTEN gene alterations are more frequent in endometrial cancer (35%), glial tumors (32%), prostate cancer (17%), melanoma (13%), non-small small-cell lung cancer (NSCLC) (12%), and breast cancer (9%) [ 63 , 64 , 65 , 66 , 67 , 68 ]. Of note, PTEN protein loss is a more frequent event in cancer, compared to PTEN genetic alterations, particularly in lung cancer and breast cancer [ 42 , 47 , 69 ]. Hence, only 9% of lung squamous cell carcinoma harbor PTEN somatic mutations, while up to 44% showed decreased protein levels [ 69 ].…”

rAAV-Delivered PTEN Therapeutics for Prostate Cancer

“…Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor gene in many kinds of carcinomas, including prostate cancer [9], liver cancer [10], breast cancer [11], lung cancer [12] and colorectal cancer [13]. In particular, a PTEN gene copy is commonly lost in prostate cancer patients with androgen-dependent PCa (ADPC) and castration-resistant PCa (CRPC) [14].…”