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As the leading cause of cancer-related mortality in the U.S. among both men and women ages 50 years and older, lung cancer is responsible for more deaths than breast cancer, prostate cancer, and colorectal cancer combined.¹ Worldwide in 2020, lung cancer accounted for some 2.2 million new cases鈥攔oughly 85% of which were non-small cell lung cancer (NSCLC)鈥攁nd 1.8 million deaths.^2-4

Traditionally, NSCLC was treated surgically, with favorable overall survival (OS) among those with early stage disease. Moreover, fractionated external beam radiotherapy (EBRT) has also been offered as a standard of care. Over the past 2 to 3 decades, however, stereotactic body radiation therapy (SBRT) emerged as an alternative approach that targets high doses of radiation with greater precision and fewer number of treatment fractions. Today, SBRT is the modality of choice for patients with medically inoperable, early-stage NSCLC, an increasing global demographic.⁴

The role of PI3K鈥怉KT鈥恗TOR in radioresistance

While SBRT is a generally effective treatment modality, some patients experience recurrence of their cancer due to intrinsic radioresistance. Indeed, rates of NSCLC recurrence have been estimated at 10% for local recurrence and up to 20% for regional or distant recurrence/progression.⁵ Aberrant DNA damage response, cell cycle redistribution, a hypoxic tumor microenvironment, autophagy, metabolic reprogramming, ferroptosis, gene mutations, and dysregulated signaling pathways have been identified as possible causes of radioresistance.⁶

Given the role of radioresistance in recurrence of early-stage NSCLC, the hunt is on to identify predictive biomarkers. In a recent study by Shen and colleagues, activation of the intracellular signaling pathway PI3K鈥怉KT鈥恗TOR was shown to mediate radioresistance.⁷ Using preclinical models derived from patients with NSCLC, the study observed elevated PI3K-AKT signaling in recurrent tumors after radiation. Shen and colleagues also found that radioresistant lung squamous cell carcinoma cells acquired elevated PI3K鈥怉KT activity, and that inhibition of downstream PI3K-AKT signaling resulted in resensitization to radiation.⁷ 

Following up on these findings, Sebastian and colleagues recently conducted a study to validate the role of PI3K鈥怉KT鈥恗TOR in radioresistance, using tumor samples from patients with T1-3N0 NSCLC who underwent SBRT at a single center.⁵ This would appear, the authors contend, to be the first clinical study to evaluate the prognostic value of gene expression signatures in early鈥恠tage NSCLC treated with SBRT.

鈥淚dentifying reasons for why patients fail after radiation therapy for lung cancer is an unmet need,鈥� says Terence Williams, MD, PhD, Professor and Chair, Department of Radiation Oncology, at City of Hope in Duarte, Calif., and the corresponding author of the new study. 鈥淲hile higher PI3K-AKT signaling has been previously linked to radiation resistance in other tumor types, there has been less evidence of its role in lung cancer, and even less evidence of its role in promoting resistance to the high-dose radiation used in SBRT.鈥�

Some novel results emerge from the data

Sebastian and colleagues isolated the pretherapy total RNA of formalin鈥恌ixed, paraffin鈥恊mbedded tumor biopsy specimens, which were then analyzed using the Clariom D assay.⁵ The authors generated risk scores from a PI3K activity signature and 4 published NSCLC signatures, which they subsequently dichotomized by the median scores. Using Kaplan-Meier and Cox regression methods, they analyzed the association of the signatures with recurrence and OS. To obtain additional validation, the PI3K signature was tested in a data set of resected NSCLC (n=361).

The study included 92 participants; survivors were followed up for a median of 18.3 months. No association was found between any of the 4 published gene expression signatures and either tumor recurrence or OS. By contrast, a high PI3K risk score was associated with greater risk of local recurrence (hazard ratio [HR] 11.72, 95% confidence interval [CI] 1.40 to 98.0; P=.023) and worse disease鈥恌ree survival (DFS) (HR 3.98, 95% CI 1.57 to 10.09; P=.0035) although was not associated with OS (HR 1.26, 95% CI 0.65 to 2.44; P=.49), regional recurrence (HR 2.74, 95% CI 0.70 to 10.68; P=.15), or distant recurrence (HR 1.05, 95% CI 0.65 to 1.69; P=.85). In the resected NSCLC data set, Sebastian and colleagues found that a high PI3K risk score was associated with decreased OS (HR 1.50, 95% CI 1.10 to 2.00; P=.013) but not with decreased DFS (HR 1.10, 95% CI 0.82 to 1.47; P=.54).

Establishing the study鈥檚 implications

What do the results of the study mean to practicing clinicians and their colleagues? 鈥淭he findings enable us to better understand which patients with stage I NSCLC stand to benefit most from surgical resection over SBRT,鈥� says Drew Moghanaki, MD, MPH, Professor and Chief of Thoracic Oncology in the department of Radiation Oncology at the David Geffen School of Medicine at UCLA. (Dr. Moghanaki wasn鈥檛 involved in the current study.)

The study further suggests that combining PI3K鈥怉KT鈥恗TOR pathway inhibition with radiation for those patients with high PI3K activity may be an effective strategy.

鈥淭his knowledge opens a potential therapeutic opportunity for targeting this pathway in combination with radiation to improve tumor control rates,鈥� Dr. Williams concluded.

Published: October 12, 2023