--- - |2- In this study, we try to understand that if we knock down some important genes like the Kirsten rat sarcoma oncogene (KRAS) and the epidermal growth factor receptor (EGFR) family in lung cancer cell lines, we could control proliferation and development of these cancer cells. Lung cancer is a leading cause of cancer‐related deaths worldwide, with less than a 5‐year survival rate for both men and women. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma oncogene (KRAS) signaling pathways play a critical role in the proliferation and progression of various cancers, including lung cancer. Genetic studies have shown that amplification, over‐expression, or mutation of EGFR is an early and major molecular event in many human tumors. KRAS mutation is a negative factor in various cancer, including non‐small‐cell lung cancer, and complicates therapeutic approaches with adjuvant chemotherapy and anti‐EGFR directed therapies. This article is dedicated to evaluating the synergistic effect of a novel EGFR inhibitor AZD8931 and KRAS small interfering RNA (siRNA) on the proliferation and apoptosis of lung adenocarcinoma cancer cells. A549 lung cancer cells were treated with KRAS siRNA and the EGFR inhibitor alone or in combination. The cytotoxic effects of KRAS siRNA and te EGFR inhibitor were determined usingMTT assay, and induction of apoptosis was determined by FACS analysis. Suppression of KRAS, Her‐2, and EGFR expression by treatments was measured by qRT‐PCR and western blotting. KRAS siRNA and the EGFR inhibitor significantly reduced the proliferation of A549 cells as well as KRAS and EGFR mRNA levels 24 hr after treatment. The results also indicated that the silencing of KRAS and EGFR has synergistic effects on the induction of apoptosis on the A549 cells. These results indicated that KRAS and EGFR might play important roles in the progression of lung cancer and could be potential therapeutic targets for treatment of lung cancer. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1560-1566, February 2019. '