PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Table 1 Pre-existing and acquired mutations implicated in clinical resistance to PAM inhibitors

Mutations implicated in clinical resistance to PAM inhibitors
PI3K Inhibitors
Agent	Type of mutations	Genes mutated	P/A prior to treatment	Type of resistance	Disease setting	References
Alpelisib	ESR1 activating mutations	ESR1 E380Q	P	Primary/Secondary	PIK3CA-mutated metastatic breast cancer	239
		ESR1 L363Q	P
		ESR1 F461V	P
		ESR1 H524L	P
		ESR1 Y537N	P
		ESR1 Y537C	P
		ESR1 D538G	P
Alpelisib	PTEN copy number loss and loss of function mutations	PTEN D97H	P	Primary/Secondary	PIK3CA-mutated metastatic breast cancer	239, 351
		PTEN L108H	P
		PTEN A126S	P
		PTEN R130*	P
		PTEN M134I	A
		PTEN	A
		L139Nfs*3	A
		PTEN T167P	A
		PTEN Q214R	A
		PTEN E242G	A
		PTEN S339fs	A
		K342_splice	A
Idelalisib	PIK3R1 inactivating mutation	PIK3R1	A	Secondary	CLL	352
Idelalisib	MAP2K1, BRAF and KRAS activating mutations	MAP2K1 Q56P	A	Primary	CLL	361
		MAP2K1	A
		E203K	A
		KRAS G13D	A
		KRAS Q22K*	A
		BRAF G469A	A
		BRAF	A
		N581_splice	A
		BRAF V600E	A
		BRAF K601E	A
Idelalisib	BIRC3 inactivating mutation	BIRC3	A	Secondary	CLL	352
mTOR Inhibitors
Agent	Type of mutations	Genes mutated	P/A prior to treatment	Type of resistance	Disease setting	References
Everolimus	Loss-of-binding/drug resistance mutation	MTOR F2108L	A	Secondary	Metastatic ATC	375

This table includes mutations and copy number changes in primary patient samples following clinical treatment with PAM inhibitors. Expression level changes in clinical samples and resistance mutations generated in cell lines or ex vivo culture models are not included
A/P Mutation absent/present, P Present (mutation present prior to treatment), A Absent (mutation absent prior to treatment), ATC Anaplastic thyroid cancer

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