LKB1 Expression Correlates with Increased Survival in Patients with Advanced Non–Small Cell Lung Cancer Treated with Chemotherapy and Bevacizumab

Abstract

LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as a potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC). We retrospectively analyzed LKB1 expression by IHC in 98 samples from 125 patients with aNSCLC, including 59 patients treated with chemotherapy and 39 treated with chemotherapy plus bevacizumab. IHC intensity was recoded in two classes (negative/weak vs. moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models. In the whole study population (125), median OS and PFS were 11.7 [95% confidence interval (CI), 9.1-15.3] and 6.7 (95% CI, 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to the treatment. Patients with negative/weak LKB1 status did not have a statistically significant benefit from bevacizumab added to chemotherapy (HR for patients treated with bevacizumab: 0.89; 95% CI, 0.51-1.56; = 0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared with those not receiving bevacizumab (HR, 0.26; 95% CI, 0.10-0.64; = 0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug. Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab. .

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer

“…Consistently, in a retrospective analysis, improved overall survival (OS) was observed among patients treated with platinum-based chemotherapy and expressing low-null levels of LKB1 protein, confirming that dysfunctional LKB1/AMPK axis may impair the capacity of tumor cell to survive following platinum-induced DNA damage [51]. In line with these results, previous preclinical findings also correlate the pathway with the response to radiation-induced DNA damage [3].…”

Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC

“…10 Based on our results, LKB1 mutations may define a more aggressive subset of KRAS-mutated NSCLC, as previously reported. 32,33 Higher aggressiveness of LKB1mutated tumors could result from the loss of LKB1 oncosuppressive function, which is involved in regulating cancer cell growth and proliferation on the basis of nutrient availability. 17 LKB1 loss, as caused by inactivating mutations or deletions of the LKB1 gene, could make cancer cells unresponsive to nutrient starvation and energetic stress, thus accelerating their growth even when nutrients (e.g., glucose, amino acid) are scarce.…”

AMPK variant, a candidate of novel predictor for chemotherapy in metastatic colorectal cancer: A meta‐analysis using TRIBE, MAVERICC and FIRE3

“…3,6 Inhibition of ATM and AMPK in cancer cells attenuate the ionizing radiation-induced G2/M cell cycle arrest. 27 Loss of LKB1 (with reduced AMPK activation) lacks the benefit of bevacizumab combined with chemotherapy in lung cancer, 28 and low phosphorylated AMPK level was associated with worse survival in mCRC treated with FOLFIRI plus bevacizumab. 29 These findings highlight the importance of the status of AMPK pathwayrelated molecules for predicting the efficacy of conventional chemotherapy in combination with bevacizumab.…”