Functional genetic dissection of KRAS biology and therapeutics

Deep mutational scanning for mutations within the KRASG12C allele that confer resistance to the covalent inhibitors sotorasib and MRTX1257 (adagrasib analogue).

Link to the paper here.

Interact with the deep mutational scanning data here.

Supplementary Information from growth in low attachment (GILA) measurements for the KRAS variants profiled in Ursu*, Neal* et al., can be found here.

KRASG12C bound to Adagrasib (PDB:6ut0)

KRASG12C bound to Sotorasib (PDB:6OIM)

Complete publication citation:

Awad, M.M., Liu, S., Rybkin, I.I., Arbour, K.C., Dilly, J., Zhu, V.W., Johnson, M.L., Heist, R.S., Patil, T., Riely, G.J., Jacobson, J.O., Yang, X., Persky, N.S., Root, D.E., Lowder, K.E., Feng, H., Zhang, S.S., Haigis, K.M., Hung, Y.P., Sholl, L.M., Wolpin, B.M., Wiese, J., Christiansen, J., Lee, J., Schrock, A.B., Lim, L.P., Garg, K., Li, M., Engstrom, L.D., Waters, L., Lawson, J.D., Olson, P., Lito, P., Ou, S.-H.I., Christensen, J.G., Jänne, P.A., Aguirre, A.J., 2021. Acquired Resistance to KRASG12C Inhibition in Cancer. New England Journal of Medicine 384, 2382–2393.

Supplemental GILA Measurements Citation:

Ursu O.*, Neal JT*, Shea E, Thakore P., Jerby-Arnon L., Nguyen L., Dionne D., Diaz C., Bauman J., Mosaad M., Fagre C., Lo A., McSharry M., Giacomelli A., Huong Ly S., Rozenblatt-Rosen O., Hahn W., Aguirre A., Berger A., Regev A., Boehm J. Massively parallel phenotyping of coding variants in cancer with Perturb-seq. Nature. Biotechnology (In press). (available on bioRxiv at.

Sponsored by the Aguirre lab at Dana-Farber Cancer Institute.