RAS GTPase family has 3 members encoding KRAS, HRAS and NRAS proteins which are involved in controlling normal growth signal. RAS GTPases are also well-known oncogenes that drive tumorigenesis when mutation is acquired. RAS oncogene mutations have been documented in more than 25% of total cancer patients worldwide and in cancer patients of Lung, Colon and Pancreas with high frequencies, especially. There were many attempts to find the effective drug to treat cancer patients with RAS mutation for last 40 years without success.

Lumakras® and Krazati®, which directly target KRAS G12C—a mutation accounting for approximately 14% of KRAS mutations—have been approved by the FDA and are currently in clinical use. More recently, the pan-KRAS inhibitor daraxonrasib reported significant efficacy in a Phase 3 clinical trial in pancreatic cancer, raising expectations for the treatment of refractory KRAS-mutant cancers. However, resistance is also emerging in patients treated with pan-KRAS inhibitors. Known mechanisms of resistance include alterations in the target itself, such as secondary mutations, activation of bypass signaling pathways, and engagement of cellular survival programs. Among these, activation of autophagy is recognized as a representative resistance mechanism within cellular survival programs.

Txinno Bioscience has confirmed that treatment with pan-KRAS inhibitors increases ULK1 expression and autophagy signaling across various KRAS-mutant cancer types. Based on reports that autophagy activation also contributes to ADC resistance, we are developing a ULK1 PROTAC as a combination partner for pan-KRAS inhibitors, as well as a ULK1 payload for dual-payload ADCs.

ULK1 is a serine/threonine protein kinase that involved in initiating autophagy process when cells encounter stressful conditions, like starvation or oxidative assaults. Autophagy has been known to play important roles in survival, drug resistance as well as immune avoidance of cancer cells. Interestingly, inhibition of ULK1 has been reported to enhance the efficacy of MEK kinase inhibitor when KRAS-mutated cancer cells were subjected to inhibition of both kinases simultaneously (Bryan D. Smith, et. al. (2019) AACR-EORTC poster presentation).

At Txinno Bioscience, we are developing ULK1 PROTAC/payloads that can be used in combination with pan-RAS inhibitors to target cancer vulnerabilities in KRAS or EGFR-mutant cancers. This combination therapy 1) can be applied to cancers with mutations other than KRAS G12C mutations, 2) can be expected to improve therapeutic efficacy at the same or lower doses of existing targeted anticancer drugs when used in combination.