Drug-resistant pancreatic cancer cell lines for drug testing

This technology is a collection of primary mouse pancreatic ductal adenocarcinoma (PDAC) cells that have developed resistance toward novel pan-RAS-GTP inhibitors, which can be used to test PDAC drugs in vitro and to understand the emergence of resistance to other RAS inhibitors.

Unmet Need: Pan-RAS-GTP-resistant PDAC cell lines for assessing the emergence of drug resistance

Current drugs that are investigated for the treatment of pancreatic ductal adenocarcinoma (PDAC) include agents that target specific RAS proteins, agents that selectively target specific mutant alleles, and agents that bind to RAS proteins selectively in the GDP-bound or GTP-bound states. However, pancreatic tumors frequently develop both intrinsic and acquired resistance to chemotherapy, which can result in the failure of initial therapies and reduce long-term survival. As pan-RAS inhibitors are likely to provoke different mechanisms of resistance than mutant-RAS-selective inhibitors, it is critical to understand how drug resistance emerges to develop new therapeutic strategies to improve patient prognosis, highlighting the need for research tools that exhibit pan-RAS resistance.

The Technology: Matched pair of pan-RAS-GTP resistant and naive PDAC cell line

This technology encompasses a collection of primary murine pancreatic ductal adenocarcinoma (PDAC) cell lines that have developed resistance against a pan-RAS-GTP inhibitor, along with their matched naive controls. Genetically engineered mice that are prone to develop PDAC were treated with a preclinical variant of a pan-RAS-GTP inhibitor that is soon entering Phase 3 trials. At first, the tumors responded, then later they developed acquired resistance to treatment. New cell lines were isolated from resistant tumors, as well as from mice that never received treatment. The sensitivity of the cell lines to the pan-RAS inhibitor was further tested in vitro and showed that the resistant lines were much less sensitive than the naive controls. Therefore, these cell lines provide a research platform that can aid in the understanding of pan-RAS resistance for drug discovery, as well as subsequent in vitro drug testing. Moreover, as the cell lines were derived from native tumors that developed resistance in vivo on a pure genetic background, these lines are suitable for implantation into an immune-competent host for in vivo testing.

Applications:

• Model systems for the study of acquired resistance to pan-RAS-GTP inhibition
• Research tool for understanding the emergence of resistance against other RAS inhibitors
• Drug screening
• Drug discovery for pancreatic ductal adenocarcinoma (PDAC)
• Identification of new therapies for drug-resistant pancreatic cancer

Advantages:

• All cell lines are on a pure genetic background
• Matched pair of pan-RAS resistant cell line and naive cell line from the same mouse
• Resistant to all RAS inhibition rather than mutant-RAS-selective inhibition
• Resistance was developed in vivo, giving a more representative model

Lead Inventor:

Kenneth P. Olive, Ph.D.

Related Publications:

• Wasko UN, Jiang J, Dalton TC, Curiel-Garcia A, Edwards AC, Wang Y, Lee B, Orlen M, Tian S, Stalnecker CA, Drizyte-Miller K, Menard M, Dilly J, Sastra SA, Palermo CF, Hasselluhn MC, Decker-Farrell AR, Chang S, Jiang L, Wei X, Yang YC, Helland C, Courtney H, Gindin Y, Muonio K, Zhao R, Kemp SB, Clendenin C, Sor R, Vostrejs WP, Hibshman PS, Amparo AM, Hennessey C, Rees MG, Ronan MM, Roth JA, Brodbeck J, Tomassoni L, Bakir B, Socci ND, Herring LE, Barker NK, Wang J, Cleary JM, Wolpin BM, Chabot JA, Kluger MD, Manji GA, Tsai KY, Sekulic M, Lagana SM, Califano A, Quintana E, Wang Z, Smith JAM, Holderfield M, Wildes D, Lowe SW, Badgley MA, Aguirre AJ, Vonderheide RH, Stanger BZ, Baslan T, Der CJ, Singh M, Olive KP. “Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.” Nature. 2024 May; 629(8013): 927-936.

Tech Ventures Reference:

• IR CU25070

• Licensing Contact: Joan Martinez