Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer PMID: 29681454

ADC Targets in Oncology

2026-04-10

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

Cell. 2018 May 3;173(4):864-878.e29. doi: 10.1016/j.cell.2018.03.028.

Elizabeth A McMillan ¹ , Myung-Jeom Ryu ² , Caroline H Diep ¹ , Saurabh Mendiratta ¹ , Jean R Clemenceau ¹ , Rachel M Vaden ¹ , Ju-Hwa Kim ² , Takashi Motoyaji ³ , Kyle R Covington ⁴ , Michael Peyton ⁵ , Kenneth Huffman ⁵ , Xiaofeng Wu ¹ , Luc Girard ⁵ , Yeojin Sung ² , Pei-Hsaun Chen ⁶ , Prema L Mallipeddi ⁷ , Joo Young Lee ² , Jordan Hanson ⁷ , Sukesh Voruganti ⁷ , Yunku Yu ⁸ , Sunho Park ⁸ , Jessica Sudderth ⁶ , Christopher DeSevo ¹ , Donna M Muzny ⁴ , HarshaVardhan Doddapaneni ⁴ , Adi Gazdar ⁹ , Richard A Gibbs ⁴ , Tae-Hyun Hwang ⁸ , John V Heymach ¹⁰ , Ignacio Wistuba ¹¹ , Kevin R Coombes ¹² , Noelle S Williams ⁷ , David A Wheeler ⁴ , John B MacMillan ⁷ , Ralph J Deberardinis ⁶ , Michael G Roth ⁷ , Bruce A Posner ⁷ , John D Minna ¹³ , Hyun Seok Kim ¹⁴ , Michael A White ¹⁵

Affiliations

1. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2. Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
3. Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Kanagawa, Japan.
4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
5. Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6. Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
7. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
8. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
9. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
10. Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
11. Translational Molecular Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA.
12. Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.
13. Hamon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
14. Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address: [email protected].
15. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].

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.

Keywords

KRAS mutant; NRF2 signaling; cancer target identification; chemical biology; ciliogenesis; glucocorticoid therapies; lung cancer; serine biosynthesis.