Targeting NAMPT and KRAS in Pancreatic Ductal Adenocarcinoma

At the 2026 American Association for Cancer Research (AACR) Annual Meeting, Asfar Azmi, PhD, shared a study that evaluated a dual targeting approach of nicotinamide adenine dinucleotide (NAD) metabolism utilizing the inhibition of nicotinamide phosphoribosyltransferase (NAMPT) and KRAS signaling using a pan-RAS inhibitor, daraxonrasib (RMC-6236), in pancreatic ductal adenocarcinoma. The NAMPT inhibitor used was RPT-E-037.

Azmi, a professor of oncology at Wayne State University School of Medicine and the director of Pancreas Cancer Research at the Karmanos Cancer Institute in Detroit, Michigan, spoke with CancerNetwork® following the meeting.

During the conversation, he was asked about several facets of the trial and shared input on what the most significant finds were, as well as why it was so important to investigate.

CancerNetwork: What was the rationale for this study evaluating a NAMPT in combination with pan-RAS targeted therapies?

Azmi: In the lab, we have been studying what happens when you expose tumors to RAS inhibitors, whether it’s daraxonrasib or other RAS inhibitors of different varieties and classes. We have consistently found that certain pathways that get activated in…response to RAS inhibition. One of the studies that we presented was about the metabolic profile changes happening when we challenge tumors with RAS inhibitors. We have found that the tumors rewired themselves, and they become highly dependent on this NAD pathway, which is a metabolic pathway. We have a drug which blocks this NAD pathway by inhibiting this enzyme NAMPT, so we then combine NAMPT inhibitors with RAS inhibitors, such as daraxonrasib and others. We found that we could have a more superior tumor healing. Then we tested it, not only in cell lines, but in advanced models of pancreatic cancer, which are called tumoroids—we also tested them in organoids—then we moved into animal studies. We found that you could have a superior regression of tumors with the combination. This drug, the NAMPT inhibitor, is right now in phase 1, so we are expecting that we would run a trial on this combination in the first quarter of 2027.

What were the primary findings of the study?

What we found is that when you expose tumors to RAS based inhibition, they revive themselves and become more dependent on the metabolic pathways. NAD is one of the drivers of resistance to RAS, so the way we target NAD is through inhibition of one of the precursor enzymes that make NAD. This enzyme is called NAMPT.

We have an agent which is called RPT-E-037, which blocks NAMPT, and this is how we shut that pathway. On one side, with daraxonrasib and other RAS inhibitors, we are shutting the RAS, and with the [RPT-E-037], we are shutting the NAD pathway. Cumulatively, when we combine these 2, there was superior tumor cell death. There was regression of tumors to a much greater extent. The mice in which we grew these tumors live longer. These findings give some idea that the combination may work. It could also prolong the anti-tumor activity of the RAS inhibitors.

One should also note that we are reducing the doses of RAS inhibitors with this combination regimen. If there are [adverse] effects—for example, rash is one of the common adverse effects daraxonrasib—with this combination, we are reducing the dose of daraxonrasib that would allow us to give it to patients in future trials. It will be a more manageable therapy, and we could prolong the treatment over a longer duration.

RMC-6236-resistant PDAC cells displayed increased sensitivity to the NAMPT inhibitor RPT-E-037 in this study. If a patient fails a pan-RAS inhibitor, what is the biological rationale for why their tumor might become more vulnerable to this metabolic blockade?

Tumors are smart. Whenever you block one path where they try to escape and go into survival mode. Researchers like us are always searching for the synthetic legal partners, where you have one dependency and you find a second dependency and try to bring combinations. When you have RAS blockade to a sufficient extent, you try to cut down the fuel supply and the escape routes. Consider NAD and NAMPT as one of the escape routes that RAS is trying to find. You put a full stop there, and you are able to block the secondary resistance mechanisms. This is how we anticipate that there will be better anti-tumor activity and more durable responses.

Beyond the presence of a KRAS mutation, are there specific metabolic markers you envision clinicians using to identify which patients would benefit most from this dual inhibition of NAMPT and KRAS?

This is a little early to say that, but we and other groups are exploring some circulatory markers in the blood, which is easy to capture. When a patient goes on RAS inhibitors, you can longitudinally get their blood samples at baseline during treatment and at the time of progression or resistance. Those are being very deeply evaluated. The first instance of resistance that people have noted is hyper activation of RAS itself. It’s an amplification of RAS, so that's one area. There are many different pathways which might be playing a role in resistance. I would say it would take another 6 months for the field to really pinpoint what the drivers of these resistances are.

References

Khan HY, Al Hallak MN, Bannoura SF, et al. Preclinical evaluation of a novel hyperbolic NAMPT inhibitor in combination with pan-RAS targeted therapies in pancreatic ductal adenocarcinoma. Presented at: 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Presentation 4579.