RB and CDKN2A cause Rapamycin resistance in cancer cells

Abstract

mTOR‐the mammalian target of Rapamycin acts as the central regulator of multiple cellular processes like cell growth, proliferation and survival by integrating signals via nutrients, growth factors, hormones and energy sensing. In cancer cells, the mTOR pathway is highly dysregulated providing survival signals to the cells for their uncontrolled growth. Hence, mTOR has been a potential therapeutic target for cancer treatment for the past two decades. Application of high micro‐molar doses of Rapamycin has been found to successfully inhibit mTORC1 by blocking the phosphorylation of both downstream substrates ‐ S6K and 4E‐BP1. Our lab previously reported that Rapamycin acts as a cytostatic drug and causes G1 cell cycle arrest in the presence of TGF‐β signal. However, in the absence of TGF‐β signal, the drug induces apoptosis. The rationale behind the apoptotic effect of Rapamycin in absence of TGF‐β is that without TGF‐β signals, cells do not arrest in G1 and progress into S phase where Rapamycin is cytotoxic rather than cytostatic. Of significance, we found that cancer cells with nonfunctional RB and mutated CDKN2A do not undergo apoptosis upon Rapamycin treatment in the absence of TGF‐β signal. Proteins encoded by RB (pRb) and CDKN2A (p16INK4A and p14ARF) are upstream effectors of E2F family of transcription factors that are critical for G1 to S phase progression.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.