Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers

Abstract

Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein Galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, Galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/Galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals Galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancer, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.

Clinical Trials and Applications of Galectin Antagonists

“…Galectin-3 expression is greatly elevated in pancreatic tumor tissue and when bound to these cells will activate the AKT pathway thereby inducing a wellestablished chemoresistance in these cells (22). In KRAS-mutant cancers (lung and pancreatic), galectin-3 has been reported to bind integrin αvβ3 and promote KRAS-mediated activation of AKT and associated chemoresistance (23,24). This observation is supported in several other studies.…”

The pervasiveness of macropinocytosis in oncological malignancies

“…As has been observed in other cancer models, only some of these tumours are dependent on oncogenic KRAS expression for their viability-a phenomenon termed oncogene addiction [56]. Recent work exploring the role of macropinocytosis in NSCLC has been in the context of KRAS addiction [28]. NSCLC dependence upon oncogenic KRAS can be mediated by cell surface receptor integrin avb3, and its modulator galectin-3.…”

Inhibition of platelet-tumour cell interaction with ibrutinib reduces proliferation, migration and invasion of lung cancer cells

“…Its ectopic expression enhanced the in vitro cell motility and invasiveness of lung cancer cells [17]. Galectin-3 is also considered a possible target for KRAS-addicted lung cancer [18]. Galectin-3 contains a collagen domain and is expressed on the cell surfaces and is thought to mediate the platelet-cancer cell interplay via binding to platelet collagen receptor GPVI [13].…”