Targeting the KRAS Pathway in Non-Small Cell Lung Cancer.
: Lung cancer remains the leading cause of cancer-related deaths worldwide. However, significant progress has been made individualizing therapy based on molecular aberrations (e.g., EGFR, ALK) and pathologic subtype. KRAS is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC), found in approximately 30% of lung adenocarcinomas, and is thus an appealing target for new therapies. Although no targeted therapy has yet been approved for the treatment of KRAS-mutant NSCLC, there are multiple potential therapeutic approaches. These may include direct inhibition of KRAS protein, inhibition of KRAS regulators, alteration of KRAS membrane localization, and inhibition of effector molecules downstream of mutant KRAS. This article provides an overview of the KRAS pathway in lung cancer and related therapeutic strategies under investigation.



The identification of oncogene-addicted cancers and specific inhibitors has revolutionized non-small cell lung cancer (NSCLC) treatment and outcomes. One of the most commonly mutated genes in adenocarcinoma is KRAS, found in approximately 30% of lung adenocarcinomas, and thus it is an appealing target for new therapies. This review provides an overview of the KRAS pathway and related targeted therapies under investigation in NSCLC. Some of these agents may play a key role in KRAS-mutant NSCLC treatment in the future.
Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
Pascale
P
Tomasini
Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
Preet
P
Walia
Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
Catherine
C
Labbe
Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
Kevin
K
Jao
Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada natasha.leighl@uhn.ca.
Natasha B
NB
Leighl
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011499:Protein Processing, Post-Translational; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
D018841:HSP90 Heat-Shock Proteins; C117307:KRAS protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
KRAS; MEK; Non-small cell lung cancer; Pathway; Selumetinib; Target; Trametinib