Background: Tyrosine-kinases (TKs) play key roles in cancer by acting as major components of various signaling pathways. Tyrosine kinase inhibitors (TKIs) act by inhibiting TKs, thereby modulating downstream signaling. Here we report a molecular pathway analysis-based approach to personalize prescription of TKIs for advanced and recurrent solid tumors, exemplified by successful cases of off-label prescriptions of TKIs to unresectable metastatic cholangiocarcinoma (MCC) and to recurrent ovarian granulosa cell tumor (GCT) patients. Methods: To isolate RNA, we used patient’s tumor histologically verified formalin fixed, paraffin embedded (FFPE) tissue blocks containing > 75% tumor cells. Gene expression levels were established using CustomArray platform. Tumor expression was compared with the corresponding normal tissues and a second-opinion platform Oncobox (Omicsway, USA) was applied for finding abnormally activated molecular pathways and for the corresponding ranking of target drugs. Results: For a 26-year-old woman with progressive ovarian GCT despite multiple previous lines of therapy who underwent salvage therapy selection, the following target drugs could be potentially most effective for treatment according to the Oncobox test: Regorafenib, Sorafenib, Sunitinib, Pazopanib, Axitinib, Imatinib. In Oct 2015, patient was administered Sorafenib, but it was not well tolerated, and this therapy was terminated after 2 months. However, ultrasound examination indicated an associated decrease in the size of neoplasms. Therapy regimen was switched to Imatinib, which was well tolerated and resulted in a disease stabilization. As for Feb 2019, Imatinib administration is continued and patient is physically active with Karnofsky scale index 90%. Another patient with MCC was prescribed with subsequent TKI monotherapies for Sorafenib and Pazopanib that occupied, respectively, 2^nd and 4^th positions of the Oncobox drug rating. It resulted in a two-year stabilization. Conclusions: Our results evidence that sequential personalized prescription of different TKIs based of gene expression tests may be a perspective avenue of further clinical investigations.