Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Development of novel chemotherapeutics is still required to enable successful treatment and improve survival for CRC patients. Here, we found that osimertinib (OSI) exhibits potent anti-CRC effects by inducing apoptosis, independent of its selective inhibitory activity targeting the EGFR T790M mutation. Intriguingly, OSI treatment triggers autophagic flux in CRC cells. Inhibition of autophagy markedly augments OSI-induced apoptosis and growth inhibition in CRC cells, suggesting a protective role of autophagy in response to OSI treatment. Mechanistically, OSI upregulates the expression of monocarboxylate transporter 1 (MCT1) and subsequently activates LKB1/AMPK signaling, leading to autophagy induction in CRC cells. Notably, OSI significantly exaggerates the sensitivity of CRC cells to the first-line drugs 5-fluorouracil or oxaliplatin. Taken together, our study unravels a novel mechanism of OSI-mediated protective autophagy involving MCT1/LKB1/AMPK signaling, and suggests the use of OSI as a potential agent for clinical CRC treatment.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and one of the leading causes of cancerrelated deaths worldwide[1]
We found that OSI significantly inhibits the growth of CRC cells by stimulating apoptosis irrelevant of its activity targeting the epidermal growth factor receptor (EGFR) T790M mutation
Since apoptosis is a major form of cell death induced by chemotherapeutic agents[20,21], we examined whether OSI could induce apoptosis in CRC cells by analyzing TUNEL-positive cells and caspase3/7 activity
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and one of the leading causes of cancerrelated deaths worldwide[1]. The standard treatment for CRC is surgery plus systematic chemotherapy regimens with or without radiation, which has shown favorable therapeutic efficacy and significantly improved the survival of CRC patients[2,3]. There is an urgent need to develop novel potential therapeutic agents for CRC treatment. Autophagy is a highly conserved process during which de novo-formed membrane-enclosed vesicles engulf aggregated proteins or damaged organelles, and subsequently fuse with lysosomes for degradation[5]. This degradation process enables tumor cells to adapt to multiple cellular stimuli such as nutrient deprivation, oxidative stress and genotoxic stress[6]. Cancer cells express high levels of transcriptional factor such as
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