Abstract Mechanical stresses, including compressive stress, are well-recognized as being inherently triggered during cancer development. They are integrated by cells in biochemical signals through mechanotransduction. However, little is known about signaling induced by compressive stress. It arises from extra-cellular matrix remodeling and tumor growth, which is overrepresented in breast and pancreatic tumors. Here, we confirmed transcriptomics data, by experimental data obtained after unidirectional 2D compression of breast and pancreatic cancer cells. Gene expression of PI3K-AKT pathway was enriched under compression in breast and pancreatic cancer cells. Compression induced the overexpression of class I PI3K members and PI3K pathway activation in these two types of cancer cells. When we added pan-PI3K inhibitor and compressive stress alone, cancer cell confluency decreased. Pan-PI3K inhibitor coupled with compression accentuated cell confluency decrease in various breast and pancreatic tumor cells, highlighting the importance of PI3K pathway for cell proliferation under compression. PI3K/AKT signaling is known to closely regulate autophagy process. The level of autophagosome protein GABARAP identified as a key PI3K transcriptional target under compression by our bioinformatics analysis was indeed modulated by compression. In conclusion, targetable mechanisms, such as PI3K signaling or autophagy process, may provide a proliferative advantage and increase cell resistance to compression.