Table 2.

Disturbances in cell signaling pathways involved in the development and progression of lung cancer.

Type	Gene and Location	Protein Name	Amino Acid Length	Molar Weight [kDa]	Function	Function in Lung Cancer	References
Cell signaling pathway stimulating cell growth	EGFR, 7p11.2	EGFR	1210	134.277	The main regulator of the cell proliferation process; Responsible for endocrine and paracrine regulation of cell growth and proliferation.	Acts as a strong oncogene in the case of deregulatory changes; Its dysregulation has been observed in 40% of NSCLC and ADC cases; Its increased expression is associated with a lower prognosis of patients.	[55,56,57,58,59]
	BRAF, 7q34	BRAF	766	84.437	A serine/threonine kinase involved in the transduction of cellular signals related to growth; Plays a key role in the regulation of MAPK/ERK signaling.	Mutations are detected in about 3% of lung cancer cases; It is a proto-oncogene; The V600 mutation in loop A is the most common type of mutation; A mutation is incompatible with RET, Ras mutations in lung cancer.	[60,61,62]
	ERBB2, 17q12	HER2	1255	137.910	It is a membrane-associated tyrosine kinase and is responsible for regulating cell proliferation.	Its mutation occurs in non-smokers; The mutation affects about 2% of lung cancer cases; It is an oncogene.	[63,64,65]
	KRAS, 12p12.1	KRAS	189	21.656	Part of the signaling of the RAS/MAPK pathway; Responsible for cell proliferation and differentiation.	It is a proto-oncogene; Mutation involved in the pathogenesis of lung adenoma; Mutations are more common in smokers and men.	[66,67,68,69]
	PIK3CA, 3q25	PIK3CA	1068	124.284	It is a kinase involved in a number of cellular functions such as growth, proliferation, differentiation, motility and secretion.	One of the most frequently mutated onco-genes along with KRAS; Relatively little information about its mutation in NSCLC; Lack of complete studies on the relationship of its amplification in lung cancer (SCLC).	[70,71,72]
	ALK, 2p32.2	ALK	1620	176.442	Plays a role in RAS activation; Participates in cellular communication and the proper development and functioning of the nervous system.	Occurs in 7% of NSCLC cases; Negative for KRAS or EGFR mutations; Mutations favor the development of ADCs; It is associated with a tendency to metastasize to the pleura and pericardium; Mutations are seen more often in women.	[73,74]
	TITF1, 14q13.3	TITF1	371	38.596	The main transcription factor necessary for the development of peripheral airways	It is a specific marker of ADC development; Can also be expressed in SCLC.	[75,76,77]
	c-MYC, 8q24.21	MYC	439	48.804	It is a transcription factor; Participates in cell proliferation and differentiation.	It is a proto-oncogene; l- and n-MYC amplification is specific to SCLC and LCNEC development.	[78,79,80]
	l-MYC, 1p34.2	MYC	364	40.327			[80,81]
	n-MYC, 2p24.3	MYC	464	49.561			[79,80,82]
Szlak genów supresorowych guza	TP53, 17p13	P53	393	43.653	Cell-cycle transcription factor; It is a kind of cellular guardian, protecting against instability and genetic abnormalities; It is also a sensor of stress signals, e.g., DNA damage, the activation of oncogenes; It is a tumor suppressor; Regulated by Mdm2 and p14ARF.	It is the most frequently mutated gene in lung cancer: 90% of SCLC and LCNEC and 50% of NSCLC; The mutation is closely related to exposure to carcinogens, especially smoking and benzopyrene; Mutations in regulatory genes: 65 cases of NSCLC were related to Mad2; the mutation in p14ARF affects SCLC, LCNEC and ADC.	[83,84,85]
	RB1, 13q14.2	Rb1	928	106.159	Tumor suppressor gene; It is an effector of p53-mediated G1/s cycle arrest via activation of p21 kinase inhibitor.	The lack of Rb protein is one of the most common escape mechanisms from the G1 checkpoint seen in SCLC; in NSCLC, hyperphosphorylation of Rb occurs; Loss of Rb occurs in 70% of LCNEC cases, 90% of SCLC cases and 15% of NSCLC cases.	[86,87,88]
	STK11, 19p13.3	STK11	433	48.636	It is a serine/threonine kinase; Acts as a tumor suppressor; Is the precursor kinase to AMPK, an essential component of cellular metabolism and the maintenance of energy homeostasis.	A mutation of this gene has been observed in ADC; It is a critical barrier to new lung formation, controls initiation, differentiation and metastasis; Typically, mutations are in smokers and are associated with a mutation in KRAS.	[89,90,91]
Szlak związany z unikaniem apoptozy	Bax, 19q13.33	Bax	192	21.184	Bcl-2 and Bax are key factors of mitochondrial apoptosis involved in the control of outer membrane permeabilization, resulting in the release of cytochrome C.	Bax heterodimerizes with Bcl-2 to control the level of susceptibility to apoptosis; Bcl-2 is overexpressed in SCLC and LCNEC and downregulated in NSCLC; Bax is downregulated in SCLC and upregulated in NSCLC; Abnormalities in the Bcl-2:Bax ratio are observed in 95% of SCLC cases and 25% of NSCLC cases.	[92,93,94,95,96]
	Bcl-2, 18q21.33	Bcl-2	239	26.266			[93,94,96,97,98]
	FASL, 1q24.3	TNFL6	281	31.485	Its interaction with the Fas transmembrane receptor (FasR) on target cells induces the course of apoptosis; Has immunoregulatory importance and is involved in the process of carcinogenesis.	Like the FasR receptor, FasL has been shown to be downregulated in 70% of NSCLC cases; In SCLC, there is no expression of FasR but high expression of FasL (50% of cases).	[99,100,101]
	E2F1, 20q11.22	E2F1	437	46.920	It is a transcription factor involved in the control of the G1/S cell cycle; Can mediate both p53-dependent and non-p53-dependent proliferation and apoptosis.	Low levels of expression are detected in NSCLC and have been suggested to increase cancer cell survival; High levels of expression are seen in SCLC and increase tumor cell proliferation.	[102]
	TERT, 5p15.33	TERT	1132	126.997	Responsible for maintaining telomere ends; It is involved in the aging process of cells.	High expression of telomerase contributes to the early stages of immortalization of cancer cells; Elevated telomerase levels are observed in 80% of NSCLC cases and nearly 100% of SCLC cases; Telomerase is expressed in checkpoint-deficient cancer cells via p53 or Rb.	[103,104,105]

Abbreviations: EGFR—epidermal growth factor receptor; BRAF—serine/threonine-protein kinase B-raf; MAP/ERK—mitogen-activated protein kinase/extracellular signal-regulated kinase ½; ERBB2—receptor tyrosine-protein kinase erbB-2; HER2—human epidermal growth factor receptor 2; RET—ret proto-oncogene; Ras—rat sarcoma virus; KRAS—Kirsten rat sarcoma virus; PIK3CA—phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; ALK—tyrosine kinase receptor; TITF1—thyroid transcription factor 1; MYC—Myc proto-oncogene protein; TP53—cellular tumor antigen p53; Mdm2—mouse double minute 2 homolog MDM2; p14ARF—ARF tumor suppressor; RB1—retinoblastoma-associated protein; STK11—serine/threonine-protein kinase STK11; AMPK—5’AMP-activated protein kinase; BAX—apoptosis regulator BAX; BCL2—apoptosis regulator Bcl-2; TNFL6—tumor necrosis factor ligand superfamily member 6; E2F1—E2F transcription Factor 1; E2F1—transcription factor E2F1; TERT—telomerase reverse transcriptase.