Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.

Graphical Abstract from McMillan et al., 2018.

Copyright © 2017 Elsevier B.V.

McMillan EA, Ryu MJ, Diep CH, Mendiratta S, Clemenceau JR, Vaden RM, Kim JH, Motoyaji T, Covington KR, Peyton M, Huffman K, Wu X, Girard L, Sung Y, Chen PH, Mallipeddi PL, Lee JY, Hanson J, Voruganti S, Yu Y, Park S, Sudderth J, DeSevo C, Muzny DM, Doddapaneni H, Gazdar A, Gibbs RA, Hwang TH, Heymach JV, Wistuba I, Coombes KR, Williams NS, Wheeler DA, MacMillan JB, Deberardinis RJ, Roth MG, Posner BA, Minna JD, Kim HS, White MA


May 03, 2018

Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.

Last updated: May 08, 2018