Chongkai Wang1, Marwan Fakih2. 1. Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA, 91010, USA. 2. Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA, 91010, USA. mfakih@coh.org.
Abstract
PURPOSE OF REVIEW: Mutations in kirsten rat sarcoma viral oncogene homolog (KRAS) are the most frequently observed genomic alterations in human cancers. No KRAS targeting therapy has been approved despite more than three decades of efforts. Encouraging progress has been made in targeting KRASG12C with KRASG12C specific covalent inhibitors in the past few years. Herein, we review the recent breakthroughs in KRAS targeting. RECENT FINDINGS: KRASG12C mutation was found in 14% of non-small cell lung cancer (NSCLC) and 3% of colorectal cancer. Recently, highly potent KRASG12C specific inhibitors have been developed and demonstrated potent activity in preclinical models. Early results from phase 1 clinical trials with sotorasib and MRTX849 show promising antitumor activity in NSCLC, colorectal cancer and other solid tumors harboring KRASG12C mutation. For the first time, the preclinical success of targeting KRAS has translated into clinical benefits, which holds the potential of transforming clinical management of KRAS mutated solid tumors. Additional efforts are needed to identify biomarkers that predict response to KRAS inhibition in patients with KRASG12C as well as to develop strategies to overcome resistance.
PURPOSE OF REVIEW: Mutations in kirsten rat sarcoma viral oncogene homolog (KRAS) are the most frequently observed genomic alterations in human cancers. No KRAS targeting therapy has been approved despite more than three decades of efforts. Encouraging progress has been made in targeting KRASG12C with KRASG12C specific covalent inhibitors in the past few years. Herein, we review the recent breakthroughs in KRAS targeting. RECENT FINDINGS: KRASG12C mutation was found in 14% of non-small cell lung cancer (NSCLC) and 3% of colorectal cancer. Recently, highly potent KRASG12C specific inhibitors have been developed and demonstrated potent activity in preclinical models. Early results from phase 1 clinical trials with sotorasib and MRTX849 show promising antitumor activity in NSCLC, colorectal cancer and other solid tumors harboring KRASG12C mutation. For the first time, the preclinical success of targeting KRAS has translated into clinical benefits, which holds the potential of transforming clinical management of KRAS mutated solid tumors. Additional efforts are needed to identify biomarkers that predict response to KRAS inhibition in patients with KRASG12C as well as to develop strategies to overcome resistance.
Authors: Rebecca L Siegel; Kimberly D Miller; Ann Goding Sauer; Stacey A Fedewa; Lynn F Butterly; Joseph C Anderson; Andrea Cercek; Robert A Smith; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2020-03-05 Impact factor: 508.702
Authors: Abdul Q Khan; Shilpa Kuttikrishnan; Kodappully S Siveen; Kirti S Prabhu; Muralitharan Shanmugakonar; Hamda A Al-Naemi; Mohammad Haris; Said Dermime; Shahab Uddin Journal: Semin Cancer Biol Date: 2018-03-07 Impact factor: 15.707
Authors: Eric Van Cutsem; Heinz-Josef Lenz; Claus-Henning Köhne; Volker Heinemann; Sabine Tejpar; Ivan Melezínek; Frank Beier; Christopher Stroh; Philippe Rougier; J Han van Krieken; Fortunato Ciardiello Journal: J Clin Oncol Date: 2015-01-20 Impact factor: 44.544
Authors: Axel Grothey; Eric Van Cutsem; Alberto Sobrero; Salvatore Siena; Alfredo Falcone; Marc Ychou; Yves Humblet; Olivier Bouché; Laurent Mineur; Carlo Barone; Antoine Adenis; Josep Tabernero; Takayuki Yoshino; Heinz-Josef Lenz; Richard M Goldberg; Daniel J Sargent; Frank Cihon; Lisa Cupit; Andrea Wagner; Dirk Laurent Journal: Lancet Date: 2012-11-22 Impact factor: 79.321
Authors: Jill Hallin; Lars D Engstrom; Lauren Hargis; Andrew Calinisan; Ruth Aranda; David M Briere; Niranjan Sudhakar; Vickie Bowcut; Brian R Baer; Joshua A Ballard; Michael R Burkard; Jay B Fell; John P Fischer; Guy P Vigers; Yaohua Xue; Sole Gatto; Julio Fernandez-Banet; Adam Pavlicek; Karen Velastagui; Richard C Chao; Jeremy Barton; Mariaelena Pierobon; Elisa Baldelli; Emanuel F Patricoin; Douglas P Cassidy; Matthew A Marx; Igor I Rybkin; Melissa L Johnson; Sai-Hong Ignatius Ou; Piro Lito; Kyriakos P Papadopoulos; Pasi A Jänne; Peter Olson; James G Christensen Journal: Cancer Discov Date: 2019-10-28 Impact factor: 38.272
Authors: Alexander Philipovskiy; Reshad Ghafouri; Alok Kumar Dwivedi; Luis Alvarado; Richard McCallum; Felipe Maegawa; Ioannis T Konstantinidis; Nawar Hakim; Scott Shurmur; Sanjay Awasthi; Sumit Gaur; Javier Corral Journal: Front Oncol Date: 2022-01-24 Impact factor: 6.244
Authors: Asimina Koulouridi; Michaela Karagianni; Ippokratis Messaritakis; Maria Sfakianaki; Alexandra Voutsina; Maria Trypaki; Maria Bachlitzanaki; Evangelos Koustas; Michalis V Karamouzis; Anastasios Ntavatzikos; Anna Koumarianou; Nikolaos Androulakis; Dimitrios Mavroudis; Maria Tzardi; John Souglakos Journal: Cancers (Basel) Date: 2022-07-07 Impact factor: 6.575