PRBB-CRG Sessions Mariano Barbacid

27/09/202412:00MARIE CURIEPRBB-CRG SessionsMariano BarbacidCentro Nacional de Investigaciones Oncológicas"Targeting KRAS Driven Cancers: A Reality after 40 Years"Host: Juan ValcarcelAbstract:KRAS oncogenes are responsible for a quarter of lung adenocarcinomas, half of colorectal carcinomas and most pancreatic tumors. First identified in 1982, they were considered undruggable until a decade ago when Shokat and co-workers identified a druggable pocket within the 3D structure of tKRAS that led to the generation and subsequent approval in June of 2021 of sotorasib, a selective inhibitor against the KRASG12C oncogenic isoform. Since then, several inhibitors capable of blocking other KRAS isoforms, including panKRAS inhibitors, have entered clinical trials. Unfortunately, their clinical performance, thus far, has been somewhat disappointing, especially in pancreatic cancer, primarily due to the rapid appearance of tumor resistance. Although the precise nature of the resistance mechanisms is still unknown, it is possible that they arise due to the limited inhibitory activity of current KRAS inhibitors since KRAS ablation in mouse lung tumor models completely prevented tumor resistance. We have reasoned that targeting KRAS oncogenic signaling at independent nodes could provide more robust tumor responses and prevent tumor resistance than just targeting KRAS itself. I will present genetic and pharmacological evidence for a therapeutic strategy that combines inhibition of three independent signalling nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS signaling pathways. Concomitant elimination of these nodes by genetic means in orthotopic mouse pancreatic tumor models results in complete and durable tumor regression, leading to tumor-free mice for at least one year. Similar results have been subsequently obtained combining selective inhibitors of a RAF1/MEK clamp (Avutometinib), a panERBB inhibitor (Afatinib) and a STAT3 PROTAC (SD36). Importantly, this triple strategy does not induce significant toxicities, at least in mice. Moreover, the efficacy of this therapeutic strategy has been validated in several patient-derived organoid (PDO) and xenograft (PDX) pancreatic tumor models. These results may open the door to the development of novel efficacious therapies for patients suffering from pancreatic tumors.