During cancer metastases, tumor cells migrate through the extracellular matrix (ECM) of connective tissues and traverse even smaller, sub-micron pores to spread to distant sites. The biophysical properties of cells, such as cellular deformability, are implicated in metastasis. In addition, tumor cells with mesenchymal phenotype tend to be more deformable than those with epithelial phenotype. Our current investigation of cellular mechanical phenotype or mechanotype builds on previously reported differences in acquired cisplatin-resistant ovarian adenocarcinoma cells. Our team screened the library of 1280 pharmacologically active compounds (LOPAC) to identify drugs that could reverse the inherent deformability of cisplatin-resistant cancer cells. We identified top hits that significantly decrease cell deformability of OVCAR5-cisplatin resistant (cisR) cells and analyze novel regulators of cellular deformability using high-throughput parallel microfiltration (PMF). We used Mergeomics, a bioinformatics approach to conduct meta-analysis across the molecular targets of the hits, their associated signaling pathways, and subnetwork neighbors, to predict regulators of cellular deformability, and validated these results experimentally. To assess cell deformability we used cellular filtration, where the percent retention represents the fraction of suspended cells retained over our micro-pore membrane filter following PMF. We confirmed the effects of key drivers in regulating cell deformability using pharmacologic and genetic manipulations. We also observed shared molecular mediators of cellular mechanotype, deformability, and invasion in breast and ovarian cancer cell lines, following treatment with another pharmacologically active agent, 4′-hydroxyacetophenone (4-HAP). 4-HAP is known to inhibit non-muscle myosin II (NM2), increasing cell stiffness and cortical tension. We discussed the functional interpretation of cellular deformability and overall cell mechanotype to obtain a mechanistic understanding of the mechanome and shared regulation of metastatic behaviors in breast and ovarian cancer cell lines. Taken together, our data revealed potential targets to modulate cellular mechanotype and highlights cell mechanical behaviors as a target for anti-cancer therapeutics.