In a new study from the Johns Hopkins Kimmel Cancer Center, researchers described a novel mechanism of tumor formation in kidney cancers driven by overexpression of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway with loss of the tuberous sclerosis complex (TSC) tumor suppressor gene. Their findings point to potential therapeutic targets for some of the most aggressive renal cell cancers.
Unopposed signaling — overactivity — through mTOR may lead to abnormal activation of a family of molecules that regulate cell growth and spread, also known as oncogenic transcription factors, specifically the microphthalmia transcription factor family (MITF).
The findings were reported Nov. 10 in Nature Communications.
The protein mTOR is important in cancer cell phosphorylation, or the activation of proteins involved in cell cycle, including cell death, DNA repair and more; and Lotan says continuously activated mTOR signaling is common in renal and other types of tumors that are prone to losing the tumor suppressor genes TSC1 or TSC2.
These transcription factors are typically inactivated in response to cellular nutrients such as amino acids. In laboratory experiments, Asrani found that this amino acid-dependent regulation of TFEB and TFE3 is actually suppressed in kidney tumor cells with TSC loss, leading to their overactivity. The combined loss of TFEB and TFE3 was enough to reduce growth of tumors with continuous mTOR signaling.
