Mutant-specific KRAS inhibitors are currently under clinical investigation. In pancreatic cancer, KRAS-G12D inhibition may prove an effective combination with immunotherapy.Credit: StudioMolekuul/ Shutterstock
The KRAS gene has been a prime target in cancer research efforts for decades. In pancreatic cancer, which is often diagnosed at an advanced stage when treatment options are limited, more than 90% of cases harbour KRAS mutations, with nearly 50% driven by KRAS-G12D.
Small molecules to target mutant KRAS have long eluded researchers because its notoriously smooth surface makes it challenging to identify pockets for a drug candidate to latch on to. “It took a long time to get something specific for a mutated version of KRAS,” says Raghu Kalluri, chair of cancer biology at The University of Texas MD Anderson Cancer Center.
Thanks to advances in medicinal chemistry and a wave of interest directed at mutant-specific KRAS inhibitors, multiple drug candidates targeting KRAS-G12D are currently under clinical investigation, including the inhibitor MRTX1133. The challenge now lies in ensuring durable efficacy.
Kalluri and colleagues have been examining the pancreatic tumour microenvironment and how it changes in response to KRAS-G12D suppression, aiming to pinpoint cells crucial to tumour shrinkage. These studies have revealed a strategy for engaging the immune system to prevent relapse.
When KRAS is off, T cells infiltrate
The team created preclinical models that closely mimic the tumour microenvironment of patients with advanced pancreatic cancer. As described in Developmental Cell, when KRAS-G12D is turned off in these models, tumours regress completely1.
“What we noticed is that the remaining pancreas, which was still functioning, recovered,” says Kalluri. “If you attack the oncogene, then the environment will reprogram itself and go back to the way it was.”
Looking closely at the pathways and cells involved revealed that oncogenic KRAS-G12D leads to the suppression of FAS protein expression, critical for cell death, on pancreatic cancer cells. In the absence of KRAS-G12D, FAS protein expression is increased, stimulating CD8+ T cells to infiltrate and eradicate the tumour.
The team then applied the KRAS-G12D inhibitor, MRTX1133, testing whether it would have the same effect as gene depletion. But although tumours exposed to the KRAS-G12D inhibitor initially regressed, they eventually returned. “A drug cannot get to every cancer cell, but the mechanism was the same,” stresses Kalluri, explaining that CD8+ T cells proved to be crucial for tumour clearance. “That’s when we gave a checkpoint blockade inhibitor.”
Detailed in Cancer Cell, the team showed in preclinical models that sustained regression of pancreatic tumours was achieved when a KRAS-G12D inhibitor was paired with immune checkpoint inhibitors2.
Two is better than one
These findings emphasize the importance of combining immunotherapy with KRAS-G12D inhibitors when studying the candidate drugs in models of pancreatic cancer. Unlike other cancer types, immunotherapies have, as of yet, demonstrated little success in pancreatic cancer3.
“The oncogenic KRAS inhibition is providing certain vulnerabilities that may make this tissue more responsive to immunotherapy,” Kalluri explains.
The robustness of the team’s discoveries, tested across 16 different preclinical models, gives Kalluri confidence that the work has translational potential. “We were quite amazed at how cells in the pancreas know to recover, repair and regenerate,” he says. “The malleability of the system and the power of regeneration is very exciting.”