Refinement in PIs therapy via synergistic approaches. PIs can be used in combination with different class of compounds for effective targeting of PI resistant cancer cells and overcoming chemoresistance. PIs can be combined with ER-stress modulators which can together cause cell cycle arrest via unfolded protein response and sometimes autophagy. Autophagy inhibitors have also shown to cause cell cycle arrest in combination with PIs thereby surpassing chemoresistance induced by PIs in alone. One more class of compounds, HDAC inhibitors have also shown promising results in combination with PIs. This combination is reported to decrease NFkB activation and induces ROS leading to cell cycle arrest in cancer cells.