Table 2 – Therapeutic opportunities created by adaptive responses to cancer therapies.

Combination therapies are organized based on therapeutic approach and the primary therapy that induced the adaptive response.

Therapeutic strategy	Primary therapy	Combination therapy partner	Cancer Type	Ref
Exploit tumor rewiring: block bypass pathway reactivation
Blocking signaling reactivation via upstream target inhibition	MTORi	IGF-1Ri	breast	111 *
Blocking multiple members of the same kinase family	PI3Kαi	PI3Kβi	breast	110
Blocking pathway activation via downstream target inhibition	BRAFi	FAKi	melanoma	106, 219 *
Blocking pathway activation via downstream target inhibition	MTORi	MAPKi	breast	220 *
Interdict stress mitigation programs
Targeting DNA damage repair checkpoints	PARPi	ATRi or WEE1i	ovarian	126 *
Blocking homologous recombination repair competency	PARPi	MEKi	ovarian	54,130
Targeting anti-oxidant to prevent adaptation to elevated oxidative stress	PARPi	TrxR1i	prostate	142
Inhibiting autophagy to prevent adaption to endoplasmic reticulum stress	multi-RTKi	chloroquine	endometrial	84
Blocking metabolic reprograming	CDK4/6i	GLS-i	breast& colorectal	138
Inhibiting anti-apoptotic proteins to target multiple stress mitigation pathways	MAPKi, PI3Ki, HER2i	BCL-XLi, MCL-1i	multiple	46,116–120,221 *
Preventing upregulation of pathway reactivation by targeting transcriptional reprograming	HER2i	BETi	breast	123
Blocking prosurvival reprogramming by targeting transcriptional activity	PI3Ki	anti-estrogen Receptor	breast	222 *
Increase therapy-induced stress
Overloading DNA damage repair pathways via chemotherapy-induced stalled replication forks	gemcitabine	PARPi	lung	148
Overloading DNA damage repair pathways via irradiation	radiotherapy	PARPi	Ewing sarcoma	149
Replication stress increased due to decreased nucleotide synthesis	PI3Ki	PARPi	breast cancer	61
Synergistic cell death via increased reactive oxygen species generation	EGFRi	HDACi	lung cancer	223
Elevated endoplasmic reticulum stress overwhelms unfolded protein response pathway	EGFRi	PDK1i	lung cancer	151
Exploit emergent vulnerabilities in the tumor ecosystem
Reactivation of CD8+ T cells that were recruited via PARPi-induced STING upregulation	PARPi	anti-PD-L1	multiple	69, 95 *
Targeting macrophages that reactivate ERK in melanoma cells via VEGF secretion	BRAFi	anti-CSF1R	melanoma	90 *
Enhancing recruitment of cytotoxic T cells by normalized blood vessels	anti-PD-1, anti-CTLA4	AGTR1i, AGTR2i	breast cancer	158, 224 *

^*References with clinical evidence of adaptive responses to the primary therapy.