It’s Got Too Greedy. New Therapeutic Options for Metabolic[ally] Addicted NSCLC?

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cancer-associated target. Second, LKB1 mutations are mutually exclusive with targetable alterations so that LKB1ness patients cannot receive TKIs targeted therapies [18]. Third, LKB1 null status has emerged as a major determinant of the 'cold' immune microenvironment in NSCLC, determining poor response to immune checkpoint inhibitors [17]. Conversely, LKB1 alterations are common events in KRAS mutant tumors [19]. After several efforts to target mutant KRAS, G12C KRAS inhibitors are undergoing early-phase clinical trials with impressive results [20,21] and will represent in the near future a turning point to treat specific KRAS mutant tumors. Nevertheless, there is cumulating evidence that in the defined subgroup of oncogenic KRAS NSCLC, 'intradriver heterogeneity' also exists [18] and the co-occurring alterations (as in LKB1 gene) could be very impactful on this aspect. In addition, other (than G12C) KRAS substitutions remain undruggable, so alternative strategies to treat these subpopulations are required.
Discovered more than 100 years ago, metabolic rewiring is more and more recognized as one of the hallmarks of cancer. Defects in cancer cell metabolism can be helpful for the diagnosis or monitoring of growth, but also for possible new treatments. The latter is of particular interest, with the notion that specific metabolic dependencies can represent a vulnerable point for different cancer types. This is witnessed by the appearance in clinical trials of inhibitors of specific metabolic pathways altered in cancer.
In this context, altered KRAS and LKB1 have been described as key factors in promoting metabolic reprogramming. In NSCLC, oncogenic KRAS promotes oxidative phosphorylation through glucose metabolism stimulation and glutamine metabolism enhancement [22,23]. LKB1 loss, instead, drives hypoxia inducible factor (HIF) signaling increase, thus promoting aerobic glycolysis and reducing oxidative phosphorylation dependency [24].
Furthermore, as our and other groups reported, the co-existence of the two alterations further accelerates cell metabolism compared to the single mutations, by exploiting both glycolysis and oxidative phosphorylation, thus rendering the tumor particularly sensitive to nutrient deprivation (as schematically represented in Figure 1) ( . Cancers 2020, 12, x 2 of 4 emerged as a major determinant of the 'cold' immune microenvironment in NSCLC, determining poor response to immune checkpoint inhibitors [17]. Conversely, LKB1 alterations are common events in KRAS mutant tumors [19]. After several efforts to target mutant KRAS, G12C KRAS inhibitors are undergoing early-phase clinical trials with impressive results [20,21] and will represent in the near future a turning point to treat specific KRAS mutant tumors. Nevertheless, there is cumulating evidence that in the defined subgroup of oncogenic KRAS NSCLC, 'intradriver heterogeneity' also exists [18] and the co-occurring alterations (as in LKB1 gene) could be very impactful on this aspect. In addition, other (than G12C) KRAS substitutions remain undruggable, so alternative strategies to treat these subpopulations are required. Discovered more than 100 years ago, metabolic rewiring is more and more recognized as one of the hallmarks of cancer. Defects in cancer cell metabolism can be helpful for the diagnosis or monitoring of growth, but also for possible new treatments. The latter is of particular interest, with the notion that specific metabolic dependencies can represent a vulnerable point for different cancer types. This is witnessed by the appearance in clinical trials of inhibitors of specific metabolic pathways altered in cancer.
In this context, altered KRAS and LKB1 have been described as key factors in promoting metabolic reprogramming. In NSCLC, oncogenic KRAS promotes oxidative phosphorylation through glucose metabolism stimulation and glutamine metabolism enhancement [22,23]. LKB1 loss, instead, drives hypoxia inducible factor (HIF) signaling increase, thus promoting aerobic glycolysis and reducing oxidative phosphorylation dependency [24].
Furthermore, as our and other groups reported, the co-existence of the two alterations further accelerates cell metabolism compared to the single mutations, by exploiting both glycolysis and oxidative phosphorylation, thus rendering the tumor particularly sensitive to nutrient deprivation (as schematically represented in Figure 1) ( .  Schematic overview summarizing the enhanced metabolic avidity and nutrient deprivation sensitivity of KRAS and LKB1 co-mutated tumors compared to wild type (WT) or single mutated NSCLCs. Violet arrows refer to glycolysis and its exploitation in the tricarboxylic acid (TCA) cycle, while green arrows represent glutaminolysis and the TCA cycle fueled by this process. The thickness of the arrows shows the dependency of the two different processes according to the different backgrounds. The black arrow represents the increase in metabolic avidity and nutrient deprivation dependency according to the different genotypes. Adapted from [25].
Altogether, this evidence clearly indicates that rapidly growing tumors, with high metastatic potential and with low response to treatment (as KRAS/LKB1 mutated NSCLCs are), are also highly dependent on nutrient availability. This offers new encouragement in this area, with the possibility to test nutrient deprivation (through low calories diets) [29] and/or metabolic inhibitors (glutaminase inhibitors, metformin, fatty acid synthesis inhibitors) in combination with chemotherapy and immunotherapy to increase the chance of survival of these patients with very low prognosis. In vitro data are particularly encouraging and new efforts should be directed in defining additional vulnerable points in the metabolic cascades in NSCLC (as well as in other cancer types) to design new, safe, and efficacious inhibitors for a rapid inclusion in future clinical trials.