May 17 2018
Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations
EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small molecules such as Gefitinib has been used for inhibiting EGFR with good initial responses; however, drug resistance is common when using a mono-targeting strategy. At present, KRAS remains an undruggable targets. As such, the development of new drugs targeting the downstream of KRAS and EGFR and their crosstalk pathways is critically needed to effectively treat NSCLC.
In recently years, they aimed to elucidate the anticancer effects of PI3K (BKM120) and MEK (PD1056309) inhibitors on NSCLC cell lines with KRAS or EGFR mutations. Inhibition of the EGFR and KRAS downstream P13K pathway using BKM120 significantly inhibited the growth of NSCLC cell lines with either EGFR or KRAS mutationslots of scientists claimed cancer cell on different metabolism way. Meanwhile, Chair Prof. Liu Liang, Prof. Yao Xiao-Jun, Dr. Leung Lai-Han and their team from the State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology, MUST). They identified a new compound D561-0775 which can inhibit NSCLC Tyrosine kinases inhibitors resistance cell growth.
In this study, significant cell cycle arrest and induction of apoptosis were observed following BKM120 treatment by Dr. Leung and her team . Notably, although the A549 and H358 NSCLC cell lines harbor the same KRAS mutation, A549 cells were less sensitive than H358 cells in the response to BKM120 treatment. Similarly, PC-9 and H1650 cells harbor the same EGFR mutation, however, H1650 was less sensitive to BKM120. Different sensitivity between NSCLC cell lines with the sameoncogenic mutation suggests that multiple crosstalk pathways exit. Combined usage of BKM120 and PD1056309 synergistically enhanced apoptosis in the A549 cells and mildly enhanced apoptosis in the H1650 and H358 cells, suggesting the crosstalk of the MEK pathway with the P13K/Akt pathways in these cell lines.
Their findings suggest that inhibition of EGFR and KRAS downstream with a P13K/Akt inhibitor could be useful for treating NSCLC. However, for NSCLC exhibiting crosstalk with other survival pathways, such as the MEK pathway, combination treatment is required. This paper was published by the journal “ONCOLOGY REPORTS”, 5 February 2016. The newly released Impact Factor for Frontiers in Oncology Reports is 2.662. (Thomson Reuters, 2018).