The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

Abstract

Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer. Review RAS GTPase overviewRAS is the most extensively studied GTPase [1] . It is known to regulate various cellular functions, including proliferation, survival, growth, migration, differentiation and cytoskeletal dynamics [2][3][4] (Figure 1). Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] . These encode the related proteins HRAS, KRAS and NRAS, respectively, of 189 amino acids in length [1,4] . KRAS exists as two isoforms, 4A and 4B, which are generated by alternative exon splicing [10] . These different RAS genes are well known to have differential cellular specificities and intrinsic transforming potentials [3,4,10] .In normal cells, RAS proteins act as molecular switches for critical cellular functions. RAS proteins are activated by upstream receptors such as receptor tyrosine kinases * To whom correspondence should be addressed. E-mail dan.theodorescu@ucdenver.edu Received 2014-08-07 Accepted 2014-10-30 Figure 1. RAS GTPase activation and downstream signaling. The cartoon shows the mechanism of RAS GTPase activation by upstream stimuli and numerous downstream effectors stimulated by activated RAS. RAS regulates critical cellular functions through these effectors. Constitutive RAS activation due to mutations leads to protumorigenic signaling through these effectors.

Analysis of Microarray Data on Gene Expression and Methylation to Identify Long Non-coding RNAs in Non-small Cell Lung Cancer

“…Guin et al . found that RalA/RalB, as the downstream effector of RAS, might be important for tumor metastasis and invasion of NSCLC, but, however, their mechanisms remained unknown25. According to our results, we speculate that high expression of ENST00000439577 could up-regulate RCC2 expression, which may promote the activity of RalA, stimulating the growth and invasion of lung tumour cells.…”

RALBP1 regulates oral cancer cells via Akt and is a novel target of miR‐148a‐3p and miR‐148b‐3p

“…Thus, contributing to cancer progression through adhesion, invasion and metastasis. Our study is an attempt to understand the role of RALBP1 in altering critical cellular activities, such as glycolysis, cellular migration, and invasion in OSCC …”

“…While RAS‐RAL axis has been investigated for non‐small cell lung carcinoma and other metastatic cancers very little of its role has been explored in oral cancers, which are also highly metastatic in nature. Through this study, we wish to ascertain (a) the role of RAL and in particular RALBP1 in promoting oral cancers (b) we wish to explore the mode of regulation of RALBP1.…”

KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma

“…Among the downstream RAS effectors, guanine exchange factors RAL (RAL A and RAL B GTPases) are also implicated in the transformation and invasion of pancreatic cancer cells. 37 , 38 Upon activation, RAL GTPase regulates numerous biological processes such as autophagy, cytokine activation, endocytosis, filopodia formation, membrane trafficking, and transcription. Abnormal regulation of these biological processes regulated by RAL can lead to proliferation, resisting cell death, cell invasion, and metastasis.…”