Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer
Authors
Elizabeth A McMillan ; Myung-Jeom Ryu ; Caroline H Diep ; Saurabh Mendiratta ; Jean R Clemenceau ; Rachel M Vaden ; Ju-Hwa Kim ; Takashi Motoyaji ; Kyle R Covington ; Michael Peyton ; Kenneth Huffman ; Xiaofeng Wu ; Luc Girard ; Yeojin Sung ; Pei-Hsaun Chen ; Prema L Mallipeddi ; Joo Young Lee ; Jordan Hanson ; Sukesh Voruganti ; Yunku Yu ; Sunho Park ; Jessica Sudderth ; Christopher DeSevo ; Donna M Muzny ; HarshaVardhan Doddapaneni ; Adi Gazdar ; Richard A Gibbs ; Tae-Hyun Hwang ; John V Heymach ; Ignacio Wistuba ; Kevin R Coombes ; Noelle S Williams ; David A Wheeler ; John B MacMillan ; Ralph J Deberardinis ; Michael G Roth ; Bruce A Posner ; John D Minna ; Hyun Seok Kim ; Michael A White
KRAS mutant ; NRF2 signaling ; cancer target identification ; chemical biology ; ciliogenesis ; glucocorticoid therapies ; lung cancer ; serine biosynthesis
Abstract
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.