Dual targeting strategy may improve treatment for resistant lung cancers

Findings from a study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) support the potential of new therapies that could improve clinical outcomes for patients with squamous and adenocarcinoma non-small cell lung cancers (NSCLC) that don't respond to immunotherapy.

Reporting in the journal Science Translational Medicine, the researchers say their study provides strong evidence for the possible effectiveness of therapies that target both lysosomes – or particles in cells that help maintain cellular stability and nutrient availability – and a protein called SREBP-1 that increases glucose uptake and helps tumors resist current therapies that inhibit lysosomes.

Corresponding and senior author for the study was Deliang Guo, PhD, founding director of the Center for Cancer Metabolism at the OSUCCC – James. Yaogang Zhong, PhD, a senior researcher in Guo's lab, was first author.

These fundings reveal a previously unrecognized mechanism by which tumors withstand lysosomal inhibition, providing a strong rationale for combination strategies targeting lysosomal function alongside glucose and lipid metabolism to more effectively treat NSCLC. This approach may also be applicable to other cancers with high metabolic demands for glucose and lipids that would present an even broader strategy for enhancing therapeutic outcomes." 

Deliang Guo, PhD, founding director, Center for Cancer Metabolism, OSUCCC – James

About the study

The scientists say that functional lysosomes are critical for tumor growth, but multiple efforts to inhibit lysosomes in several cancer types with a drug called chloroquine (CQ) in combination with radiation, chemotherapy and targeted agents have yielded only modest or partial responses in clinical trials.

This preclinical study, which involved cell lines and animal models, sought to learn how tumor cells evade lysosomal suppression, and also identify strategies for overcoming this resistance.

Researchers also demonstrated that inhibiting glucose transport overcomes tumor resistance to CQ treatment by inducing mitochondrial damage, oxidative stress and tumor cell death.

"Our study is the first to reveal a previously unrecognized mode in which glucose and lipid metabolism are coupled to form a positive feedback regulatory loop," said Guo. "This finding deepens our understanding of the regulation of complex metabolic networks in biological systems and uncovers the metabolic compensatory flexibility of tumors, as well as their ability to evade inhibition of a single metabolic node."

"This study provides clear mechanistic guidance and a feasible drug-combination strategy to markedly enhance the antitumor efficacy of lysosomal inhibitors," said Zhong, adding that this work proposes that simultaneous targeting of lysosomal function and the glucose-lipid metabolic positive feedback loop represents an efficient antitumor strategy.

"This approach is particularly suitable for patients with lung squamous cell carcinoma and subsets of lung adenocarcinoma who lack actionable driver mutations and have limited treatment options," said Zhong.

Notably, CQ and simvastatin are both clinically approved, repurposed drugs. The fatty acid synthesis inhibitor TVB-2640 has already entered phase II/III clinical trials, greatly accelerating the feasibility of clinical translation and the validation of this combination therapy strategy.

Other study co-authors from Ohio State are Feng Geng, PhD; Huali Su, PhD; Logan Mazik; Na Li; Chengyao Chiang, PhD; Jeffrey Tonniges, PhD; Xiaoqui Mo, PhD; Amy Webb, PhD; Yongchen Guo, PhD; David Carbone, MD, PhD; Junran Zhang, MD, PhD; Arnab Chakravarti, MD; Qi-En Wang, PhD.