Activated KRAS, polyamines, iASPP and TME: a multiple liaison in pancreatic cancer

The treatment of pancreatic ductal adenocarcinoma (PDAC) is one of the most unmet clinical needs in oncology. Indeed, PDAC is the most common and lethal malignancy of pancreatic cancer with a 5-year survival rate under 5%. The majority of cases are unresectable and combined systemic therapy is offered as a palliative option. PDAC-related mortality is expected to surpass breast and colorectal cancers by 2030, making PDAC one of the malignancies with the greatest number of unfulfilled needs for innovative therapy [1]. PDAC tumors are characterized by a high degree of fibrosis, believed to be a major contributor to their therapy resistance. Besides KRAS mutations that appear to occur at early stages, TP53 mutations are strongly associated with poor outcome [2–5]. A recent phase III adjuvant trial using gemcitabine has shown that TP53 mutations were a negative prognostic factor for disease-free survival in untreated patients. Interestingly, they were a positive predictive factor for gemcitabine efficacy [6]. These observations suggest that TP53 mutation status and targeting may inform improved personalized therapy strategies in PDAC patients [7–10].

Kalaany’s group recently reported cutting-edge evidence addressing the question whether in PDAC cells, glutamine derives from a distinct source rather than arginine-derived ornithine, which might produce polyamines fueling aberrant tumor growth [11] (Fig. 1). Moreover, they identified ornithine aminotransferase activity (OAT) as the leading molecular activity driving polyamine synthesis and sustaining PDAC tumor growth. Mutant KRAS transcriptionally activates OAT and enzymes involved in polyamine synthesis, thereby linking one of the most frequent genetic alterations in PDAC to this metabolic dependency. Notably, this OAT directional activity is specifically in infant and not adult tissues, thus highlighting that the therapeutic tackling of OAT-induced dependency of PDAC cells might not have any toxic effects on non-tumoral surrounding cells. Frequently, KRAS and TP53 mutations are concomitantly found in PDAC patients, highlighting the possibility of an oncogenic cross-talk governed either by direct physical interaction or by indirect events. Undoubtedly, the identification of cancer metabolic vulnerabilities such as that originally proposed by Kalaany’s group in PDAC reinvigorates the use of drugs targeting metabolism that has been limited from both cancer metabolic plasticity and high toxicity. The reported findings do not rule out the possibility that alternative pathways of polyamine production will be envisaged by PDAC cells but intriguingly might minimize toxic effects of anticancer metabolic treatment. PDAC cells are embedded in a rather peculiar tumor microenvironment (TME) that includes a wide range of fibroblasts and immune cells. Very little is known about the bi-directional cross-talk between TME cellular landscape and PDAC cells. Unlike other tumor types, evidence that PDAC is one of the prototypes of a metabolic tumor is robust, consequently the rationale for implementing precision oncology approaches based partially on re-wiring its metabolism is very attractive and potentially holds great therapeutic promise. The reported findings indicate that a lack of arginine in TME as a source for polyamine production rewired PDAC cell metabolism instigates the use of glutamine unlike arginine that is rather abundant in the pancreatic TME. Is the uneven ratio between arginine and glutamine in PDAC TME able to signal mutant KRAS to promote its transcriptional activation on OAT gene expression? Unfortunately, KRAS mutations, except for KRAS G12C, which is most frequently altered in non-small lung cancers than in PDAC, are still undruggable, thereby limiting the possibility of combining ODT-inhibitors therapeutically such as 5-fluoromethylornithine (5-FMO) with those targeting mutant KRAS. Despite this, the attempt to pre-clinically evaluate the anticancer effects of the combination of either sotorasib or adagrasib in vitro and in vivo since KRAS G12C inhibitors with 5-FMO would be extremely valuable in potentially providing a therapeutic rationale for the reported findings.

Fig. 1. Reciprocal cross-talk between RAS mutations in PDAC cells and the surrounding TME.

In the left panel, the role of ODT in polyamines synthesis is resumed accordingly to the data reported by Kalaany’s group. In the right panel, the role of iASSP in KRAS G12D and KRAS G12D/mutant p53^R172H is depicted accordingly to the data reported by Lu’s group.

In the present issue of Cell Death and Differentiation, Lu’s group together with her collaborators elegantly unveil a new role of iASPP, a wt-p53 suppressor [12], which exerts anti-inflammatory and tumor suppressor activities on KRAS G12D-induced or KRAS G12D/mutant P53^R172H PC onset. Indeed, iASPP depletion in vivo favors inflammation, acinar to ductal metaplasia and PDAC insurgence [13]. Notably, either iASPP deletion or p53 mutations affect overlapping gene patterns that include NFkB and AP1 transcriptional-regulated inflammatory genes thereby providing molecular insights for the iASPP anti-inflammatory and tumor suppressor activities on PDAC onset (Fig. 1). Interestingly, higher levels of iASPP transcript are associated with good prognosis of PC patients. As PDAC TME appears to be critical for its aggressive malignancy as well as its refractoriness to standard anticancer therapies, Lu’s group along with his collaborators investigated the impact of iASPP’s inflammatory role of shaping the TME of both KRAS G12D and KRASG12G/mutant P53^R172H in vivo models. Upon iASPP depletion, they found aberrant production of pro-tumorigenic cytokines such as GM-CSF, CCL2, CCL5, IL1-α and IL1-β and other inflammatory factors. This effect was paired with an increased infiltration of B, CD4, CD8 and Treg cells, consequently framing the pro-tumorigenic cytokine release into a rewired and permissive immune landscape. iASPP anti-inflammatory activity exhibited pancreatic tissue specificity, thus reinforcing its critical role as a pancreatic tumor suppressor gene.

Altogether, the findings reported by both Kalaany’s and Lu’s groups raise a few implications on the main features of PDAC. Firstly, both KRAS and TP53 mutations that are among the most frequent and difficult ones to tackle therapeutically play a critical role as regulators of metabolic plasticity and re-wiring of PDAC cells. Secondly, pancreatic TME whose clinical relevance in the poor response of PDAC to anticancer treatment which has already been highlighted, requires further investigation as it is a reservoir of unprecedented information that might allow us to design novel therapeutic approaches for PDAC treatment. It is important to note that one of the issues emerging from the reported data is whether the type of KRAS alteration is representative of all the range of KRAS mutations in PDAC, as this could have important implications for the precise treatment of PDAC patients. In spite of this, there is growing evidence that co-mutations have an impact on prognosis and response to therapy of a given cancer type. Here, iASPP anti-inflammatory activity functions in both KRAS G12D and KRAS G12D/mutant p53^R172H mice provide further evidence that its activities might counteract early genetic alterations such as KRAS mutations in PDAC onset. If either TP53 or other co-mutations accompanying KRAS alterations contribute to depleting arginine from PDAC TME thereby instigating unconventional ODT-mediated glutamine production remains to be elucidated. Since only 20% of cancer patients carry druggable genetic alterations, the majority of them are treated with conventional chemo-radiotherapy. There is an urgent need to translate the findings of exploratory research on the RNA expression layer toward clinical applications. To date, unprecedented development technologies have allowed us to mark almost each cell type transcriptomically, including tumoral and non-tumoral ones, which are present in the cellular landscape of a specific tumor (single-cell sequencing). We are able to identify gene expression signatures that strongly contribute to stratify cancer patients predicting their survival and response to treatment [14–16]. In addition, targeting specific genes of the signature either by drugs impacting their gene product activities or synthetic molecules interfering at the transcript level may hold great therapeutic potential.

Last but not least, tumor progression and metastatization do not necessarily lead to an increased complexity when compared to the primary tumor, thus suggesting that a poor response of the metastatic lesion to treatment might result from the selection of a restricted number of pathways that allow metastatic cells surviving stressful conditions and hence becoming resistant to anticancer treatment [17–19]. The core of restricted pathways might also involve those only activated or repressed during development and consequently confined to infant and not adult tissues, similar to ODT-induced metabolic plasticity in the PDAC onset. If cancer progression can resemble, at least in part, a development disorder requires further elucidation.

Author contributions

GB wrote the manuscript.

Funding

This work has been supported by the MUR-PNRR M4C2I1.3 PE6 project PE00000019 Heal Italia (CUP: H83C22000550006) to GB.

Competing interests

The author declares no competing interests.